Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][OH:38]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN(C)CCO
Product: CNc1ncnc2c1nc(OCCN(C)C)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)-purin-9-yl)phenyl]urea and 2-(dimethylamino)ethanol by the same techniques as in Example 136.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: CN1CCNCC1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1cccc(F)c1
Yield: 44 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and N-methylpiperazine to give the title compound in 44% yield; NMR Spectrum: 2.10 (s, 3H), 2.50 (s, 4H), 2.78 (t, 2H), 3.80 (s, 3H), 4.42 (t, 2H), 5.12 (s, 2H), 7.00 (d, 1H), 7.16 (m, 2H), 7.23 (m, 2H), 7.38 (d, 1H), 7.44 (q, 1H), 8.25 (s, 1H), 8.44 (s, 1H); Mass Spectrum: 508 (MH+).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:7]=1[CH2:8][O:9][CH2:10][C:11]#[C:12][CH2:13]Br>O1CCCC1.C(Cl)Cl>[CH:1]1([NH:4][CH2:13][C:12]#[C:11][CH2:10][O:9][CH2:8][C:7]2[CH:15]=[C:16]([Br:19])[CH:17]=[CH:18][C:6]=2[F:5])[CH2:3][CH2:2]1
Reactant: Fc1ccc(Br)cc1COCC#CCBr
Reactant: NC1CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Fc1ccc(Br)cc1COCC#CCNC1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A solution of cyclopropylamine (1.10 ml, 15.8 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)but-2-ynyl bromide (530 mg, 1.58 mmol) in tetrahydrofuran (8 ml). The cloudy reaction mixture was stirred for about thrity minutes. The reaction mixture was then cooled to 0° C., and held at this temperature for about four hours, at which time no starting material remained, as determined by thin layer chromatography. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 1 M potassium carbonate (10 ml). The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The resulting oil was further purified by preparative high performance liquid chromatography, affording 362 mg (73%) of the title intermediate as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[O:11][CH2:12][CH2:13][C:14](O)=[O:15])=[O:7])=[CH:4][C:3]=1[C:24]1[CH:25]=[N:26][C:27]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:29]=1[C:30]#[N:31].[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH2:45])([CH3:39])([CH3:38])[CH3:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:36]([O:40][C:41](=[O:46])[NH:42][CH2:43][CH2:44][NH:45][C:14](=[O:15])[CH2:13][CH2:12][O:11][C:10]1[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[C:3]([C:24]2[CH:25]=[N:26][C:27]([C:32]([F:34])([F:35])[F:33])=[CH:28][C:29]=2[C:30]#[N:31])[CH:4]=1)[CH3:21])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionic acid 11-4 (50 mg, 0.10 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (51.5 mg, 0.54 mmol) in DMF (500 μL), EDCl (22 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA (34 μl, 0.19 mmol) were added. The mixture was stirred for 48 hrs at rt, diluted with MeOH (500 μL) and purified by prep HPLC to afford {2-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propionylamino]-ethyl}-carbamic acid tert-butyl ester. After treatment with 50% TFA in DCM (1 mL) for 2 hrs, followed by concentration in vacuo, N-{2-[2-(2-amino-ethylcarbamoyl)-ethoxy]-phenyl}-4-chloro-3-(4-cyano-trifluoromethyl-pyridin-3-yl)-N-methyl-benzamide 53-1 was obtained. MS [M+H]+546.1; tR=5.66 min (method 2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1CCCC1>C1(C)C=CC=CC=1.CCOCC>[C:11]12([CH2:9][C:8](=[O:10])[C:3]3[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=3)[O:1]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2
Reactant: CC(=O)c1ccccc1O
Reactant: O=C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCNC1
Product: O=C1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 2′-hydroxyacetophenone (Aldrich, CAS# 118-93-4, 2.72 g, 20 mmol), cyclohexanone (2.7 mL, 26.1 mmol), and pyrrolidine (1.66 mL, 19.9 mmol) was stirred in 6 mL toluene at room temperature for 1 h and at reflux (Dean-Stark trap) for 4 h. After cooling to room temperature, the mixture was diluted with ether (30 mL), washed sequentially with 2N HCl (10 mL), 2NNaOH (10 mL), and H2O (10 mL), dried over Na2SO4, and filtered. Evaporation of volatiles in vacuo afforded the crude title compound, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Br)cn1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(Br)cn1
Temperature: 70 °C
Yield: 97.9 %

Procedure:
A mixture of 2-((5-bromopyridin-2-yl)methyl)isoindoline-1,3-dione from Step 1 of Example 265 (630 mg, 1.987 mmol) and hydrazine monohydrate (0.484 mL, 9.93 mmol) was heated to 70° C. for 1.5 hr. A thick suspension formed. after cooling to rt, the reaction mixture was diluted with 20 ml of EtOH, filtered and the filter cake was washed with EtOH. The filtrate was concentrated to ⅓ volume and was refiltered. Concentration of that filtrate afforded (5-bromopyridin-2-yl)methanamine (364 mg, 1.946 mmol, 98% yield) as a colorless semisolid. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.2 Hz, 1H), 7.99 (dd, J=8.4, 2.4 Hz, 1H), 7.45 (dd, J=8.4, 0.4 Hz, 1H), 3.77 (s, 2H). MS (ES+) m/z: 187.12, 189.07 (M+H); LC retention time: 0.298 min (analytical HPLC Method O).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1>CCO.[Pd]>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O)c(N)n1
Reaction time: 16 h
Yield: 99.5 %

Procedure:
3-Hydroxy-6-methyl-2-nitropyridine from Example 117a (10.5 g, 68 mmole) was combined with 10% Pd/C (100 mg) in EtOH (100 mL), and the mixture was stirred under a H2 atmosphere for 16 hours. The mixture was filtered and concentrated to yield 8.40 g (99% ) of the title compound. mp 141-145° C. 1H NMR (DMSO-d6, 300 MHz) δ: 2.14 (s, 3H), 6.22 (d, J=7.5 Hz, 1H), 6.71 (d J=7.5 Hz, 1H). MS (DCI/NH3) m/e 125 (M+H)+, 142 (M+NH4)+.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@H:5]1[F:17])=[N+]=[N-]>[Pd].C1COCC1.CCO>[NH2:1][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@H:5]1[F:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@H](F)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](F)C1
Reaction time: 2 h
Yield: 35.7 %

Procedure:
Palladium on carbon (10%, 0.876 g, 0.823 mmol) was added to a solution of (cis)-tert-butyl 4-azido-3-fluoropiperidine-1-carboxylate (2.01 g, 8.23 mmol) dissolved in THF and EtOH (1:1, 82 mL). The reaction was placed under a hydrogen atmosphere (balloon pressure) and stirred for 2 hours. The mixture was filtered through GF/F paper and concentrated in vacuo. The amine was purified on a Varian Bond Elut SCX column, eluting with methylene chloride followed by a solution of MeOH containing 6% aqueous NH4OH. The second eluant was concentrated in vacuo to provide the desired product (642 mg). MS ESI (+) m/z 218.8 (M+1) detected.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C#N)ccc43)nc2c1
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (From Ex 14, step 5, 50 mg, 0.11 mmol) in methanol (20 mL) and water (1 mL) was added lithiumol hydroxide (10 mg, 0.40 mmol) with stifling overnight at room temperature. The resulting mixture was concentrated under vacuum, dissolved in water (10 mL) and adjusted to 7 with AcOH, collected by filtration to give 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (14.7 mg, 30%). [M+H]+ 425.1
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].BrC[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)=[CH:12][C:11]=1[CH3:29].[CH3:30]N(C=O)C>>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=3)=[C:12]([CH3:30])[C:11]=2[CH3:29])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CBr)c(C)c2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C#Cc2ccc(-n3ccnc3)c(C)c2C)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of imidazole (30.0 mg, 0.44 mmol) in 2 mL DMF was treated with NaH (11.0 mg, 0.44 mmol) and heated to 90° C. After 1 h a solution of ethyl 4-(4-bromomethyl-3-methyl-phenylethynyl)-benzoate (Intermediate 137, 120.0 mg, 0.34 mmol) in 2 mL DMF was added and stirring at 90° C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 90.0 mg (71%) was isolated by column chromatography (20-100% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]([C:14](Cl)(Cl)[Cl:15])([F:13])([F:12])[F:11].C(OC(=O)C)(=O)C>CN(C=O)C.O.[Zn]>[Cl:15][C:14]([C:10]([F:13])([F:12])[F:11])=[CH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C=C(Cl)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 390.7 %

Procedure:
12 g of p-tolualdehyde dissolved in 20 cc of DMF and 7.5 g of Zn are charged to a flask of 250 ml of capacity. 2.5 g of CF3CCl3 is dropwise added and the resulting reaction mixture is slightly heated until the reaction turns into strongly exothermic. Then 10 g of CF3CCl3 dissolved in 100 cc of DMF is dropwise added and the resulting mixture is stirred at room temperature for 4 hours. 10 cc of acetic anhydride and 13 g of Zn are then added. After 2 hours at room temperature, the reaction mixture is poured in acidic water and is extracted three times with ether; the ether phases are combined with one another, and are washed with a saturated solution of sodium bicarbonate, and with brine, and are then thoroughly dried and evaporated. The raw reaction product is chromatographed on silica (98/2 hexane/ethyl acetate). 11.5 g of 4-(2-chloro-3,3,3-trifluoroprop-1-enyl)-toluene is obtained.
Reaction SMILES: O1CCOC1[N:6]1[N:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[N:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[NH:7]1.[C:23](=O)(O)[O-:24].[Na+]>O1CCCC1.Cl.[Cl-].[Na+].O>[CH3:14][S:11]([C:9]1[N:8]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([CH:20]=2)[CH:23]=[O:24])[N:7]=[N:6][N:10]=1)(=[O:12])=[O:13]
Reactant: O=C([O-])O
Reactant: COc1ccc(N2NN(C3OCCO3)N=C2S(C)(=O)=O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C=O

Procedure:
1-(3-[1,3]Dioxolan-2-yl(4-methoxy-phenyl)-5-methanesulfonyl-1H-tetrazole (800 mg) in tetrahydrofuran (13 ml) and hydrochloric acid (2N, 7.5 ml) was stirred at room temperature for 1.5 h. The solution was basified with sodium bicarbonate solution (8%), saturated with brine (50 ml), extracted with ether (3×50 ml), dried (Na2SO4) and evaporated to give the title compound as an orange solid (307 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4](Br)=[CH:5][CH:6]=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[C:21]([O-:24])([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>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:2]2[S:3][C:4]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[C:15]([O:24][CH3:21])[CH:14]=3)=[CH:5][CH:6]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(-c3ccc(OC)c(OC)c3)s2)cc1OC
Temperature: 90 °C

Procedure:
To a solution of 2,5-dibromothiophene (14) (242 mg, 1 mmol), (3,4-dimethoxy phenyl)boronic acid (15) (455 mg, 2.5 mmol), and Pd(PPh3)4 (58 mg, 0.05 mmol) in dioxane (10 mL) was added Na2CO3 (12 mL, 2.0 M aqueous solution). The resultant mixture was purged with nitrogen and stirred rapidly while heating at 90° C. overnight. The reaction mixture was cooled to 23° C., acidified with 1M HCl and extracted with EtOAc. The combined organic extracts were washed with H2O, dried over MgSO4, filtered and concentrated under reduced pressure. 2,5-bis(3′,4′-dimethoxyphenyl)thiophene (16) was obtained quantitatively as a green-yellow solid after the purification by column chromatography (10%-20% EtOAc in hexanes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[CH3:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([CH2:51][CH3:52])=[N:49][N:50]=2)=[O:43])=[CH:18][C:17]=1[CH3:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Reactant: CCc1nnc(N)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nnc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C)c2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-methylaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-ethyl-1,3,4-thiadiazole (43 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was, dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 71 mg of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N:33]1[CH:37]=[C:36]([C:38]#[N:39])[N:35]=[CH:34]1)=[O:6])[CH:2]=[CH2:3].[F:40][C:41]([F:48])([F:47])[S:42]([O:45]C)(=[O:44])=[O:43]>ClCCl>[F:40][C:41]([F:48])([F:47])[S:42]([O-:45])(=[O:44])=[O:43].[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]2[C@H:19]([CH3:20])[C@H:18]3[N:15]([C:16](=[O:24])[C@@H:17]3[C@H:21]([OH:23])[CH3:22])[C:14]=2[C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:9][C@H:8]1[CH2:31][CH2:32][N+:33]1[CH:37]=[C:36]([C:38]#[N:39])[N:35]([CH3:41])[CH:34]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CCn3cnc(C#N)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC[n+]3cc(C#N)n(C)c3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-cyanoimidazol-1-yl)ethyl}-pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (7.56 g) in dichloromethane (110 ml) was added methyl trifluoromethanesulfonate (3.1 ml) at room temperature and the solution was stirred at the same temperature for 30 minutes. The solvent was evaporated to give allyl (4R,5S,6S)-3-[(2R,4S)-1-allyloxycarbonyl-2-{2-(4-cyano-3-methyl-1-imidazolio)ethyl}pyrrolidin-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate trifluoromethanesulfonate (10.4 g) as a yellow paste. This compound was immediately used as the starting compound for the next step.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:24]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][CH:22]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 409.15 g/mol.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.O=[C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1>C(O)(=O)C.O>[CH3:2][O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][C:14]2=1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C1CCc2[nH]c3ccc(OC)cc3c2C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
(4-Methoxyphenyl)hydrazine hydrochloride (80.0 mg, 0.46 mmol) and methyl 4-oxocyclohexanecarboxylate (85.9 mg, 0.55 mmol) were dissolved in acetic acid (0.5 mL). The mixture was heated at 80° C. with stirring under nitrogen for 3 h, cooled, diluted with water (2 mL) and the resulting precipitate was collected by filtration, gently washed with water and dried in vacuo to yield the title compound (107 mg, 90%) as an off-white solid. C15H17NO3, Mr=259.30; 1H NMR (400 MHz, DMSO-d6) d: 1.81-1.91 (m, 1H), 2.15-2.19 (m, 1H), 2.66-2.84 (m, 4H), 2.90 (dd, J=4.6/14.2 Hz, 1H), 3.65 (s, 3H), 3.72 (s, 3H), 6.61 (dd, J=2.4/8.8 Hz, 1H), 6.86 (d, J=2.4 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 10.51 (s, 1H); LCMS (ESI) tR: 2.27 min (>99%, ELSD), m/z: 260.2 [M+1]+.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([OH:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].O[C:26]1[CH:39]=[CH:38][C:29]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:28][CH:27]=1>C(O)(C)C>[C:19]([O-:24])(=[O:23])[C:20]([CH3:22])=[CH2:21].[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:31])[C:29]1[CH:38]=[CH:39][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Product: C=C(C)C(=O)[O-]
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In the following example, a terpolymer derivative having 0.88 mole % methacrylate and 0.07 mole % benzophenone (graft ratio 92.7%:7.3% methacrylate:benzophenone) was prepared by a procedure to Example A-3 except that the tetrabutylammonium salt was prepared by charging 101.3 mL tetrabutylammonium hydroxide (1.0 M in methanol), 8.3 g (8.2 mL) methacrylic acid, 1.01 g 4-hydroxybenzophenone, and 100 mL isopropanol to a second flask and stirring at room temperature to give a translucent yellowish solution. This mixture was then added to the polymeric cement, as in Example 4. The polymer was isolated by precipitation in isopropanol with 0.1% BHT stabilizer optionally added. 1HNMR (400 MHz, CDCl3) analysis confirmed 97.3% conversion of benzylic bromide to grafted species. These results are given in Table A.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:28]2[CH:29]=[CH:30][C:31]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:33]=2)[O:20][Si](CC)(CC)CC)[CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(O)(=O)C.C(OCC)(=O)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[C:3]([O:14][CH2:15][CH2:16][NH:17][CH2:18][CH:19]([C:28]2[CH:29]=[CH:30][C:31]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:32]([NH:34][S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])[CH:33]=2)[OH:20])[CH:2]=1
Reactant: CC[Si](CC)(CC)OC(CNCCOc1ccc2c(c1)oc1ccccc12)c1ccc(OCc2ccccc2)c(NS(=O)(=O)N(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)Nc1cc(C(O)CNCCOc2ccc3c(c2)oc2ccccc23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 60.1 mg of Intermediate 43 in 2.9 ml of anhydrous tetrahydrofuran, 36.8 μl of acetic acid and 574 μl of 1 M solution of tetrabutyl ammonium fluoride in tetrahydrofuran were added and the mixture was agitated at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, followed by drying, whereupon the solvent was distilled off under a reduced pressure. The resulting residue was purified by a silica gel chromatography,whereupon the above-identified compound (50.0 mg) was obtained from eluted fractions with methanol/chloroform (7/100). Rf=0.39 (methanol/chloroform of 1/10).