Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([NH2:6])=[O:5].C([Si](C)(C)[O:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:31])(C)(C)C.S([O-])(O)=O.[Na+].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C)C(=O)C.O.C1COCC1.CO>[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([C:26]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=3[CH3:12])[N:1]=2)=[CH:24][C:23]=1[CH3:31]
Reactant: Cc1cc(C)c(C(N)=O)c(N)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])O
Agent: [F-]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 155 °C
Reaction time: 14 h
Yield: 23.7 %

Procedure:
A mixture of 2-amino-4,6-dimethyl benzamide (0.2 g, 1.22 mmol), 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,5-dimethyl-benzaldehyde (0.376 g, 1.22 mmol), sodium hydrogensulfite (0.22 g, 1.22 mmol) and prtoluenesulfonic acid (0.116 g, 0.61 mmol) in N,N-dimethyl acetamide (10 mL) was stirred at 155° C. for 14 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The solid crashed out and was collected by filtration to afford impure product. The solid was re-dissolved in THF (30 mL) and mixed with TBAF in THF (5 mL, 5 mmol). The reaction mixture was stirred at room temperature for 14 h and concentrated using a rotary evaporator to afford an oily residue. Further purification by column (SiO2, EtOAc/DCM/MeOH=12:4:1) yielded an off-white solid. This solid was diluted with MeOH (10 mL) to make a slurry. The solid was collected by filtration and washed with MeOH to afford 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethylquinazolin-4(3H)-one (98 mg, 24%) as a white solid. Selected data: MS (ES) m/z: 339.10; MP 259.6-261.2° C.
Reaction SMILES: [H-].[Na+].C1(NN)C=CC=CC=1.C(=O)C.C1(C(Cl)=O)CCCCC1.Cl.[CH:24]1([C:30]([N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)N)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[CH2:40]1[CH:46]([C:47]([OH:49])=[O:48])[CH2:45][CH2:44][C:42](=O)[CH2:41]1>O.C(O)(=O)C.CN(C)C=O>[CH:24]1([C:30]([N:32]2[C:42]3[CH2:41][CH2:40][CH:46]([C:47]([OH:49])=[O:48])[CH2:45][C:44]=3[C:39]3[C:34]2=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NN(C(=O)C1CCCCC1)c1ccccc1
Reactant: O=C1CCC(C(=O)O)CC1
Agent: CC=O
Agent: Cl
Agent: O=C(Cl)C1CCCCC1
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)C1CCc2c(c3ccccc3n2C(=O)C2CCCCC2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 3.88 g. of sodium hydride in 100 ml. of dimethylformamide was added portionwise 20 g. of acetaldehyde phenylhydrazine, stirring was continued for 2 hours, 22 g. of cyclohexanecarbonyl chloride was added dropwise, stirring was continued for three hours and the reaction mixture was then poured into ice water containing acetic acid. The aqueous mixture was extracted with ether and the ether extract was washed with water, dried and evaporated to dryness. The residue was taken up in absolute ethyl alcohol and ether, hydrogen chloride in ethyl alcohol was added, and the solution was allowed to stand 1 hour, chilled, and evaporated to dryness under reduced pressure. The residue was triturated with ethyl acetate and the resulting solid was filtered to yield 9.2 g. of 1-cyclohexanecarbonyl-1-phenylhydrazine hydrochloride; m.p. 170°-172°C. This was combined with 5.5 g. of cyclohexanone-4-carboxylic acid in 100 ml. of glacial acetic acid and the mixture was heated at the boiling point for 1 hour, diluted with 50 ml. of water and chilled. The resulting precipitate was collected by filtration, washed with 75% acetic acid in water and dried to yield 3.9 g. of the title compound; m.p. 157°-159°C.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[H-].[Na+].[C:9]([O:12][C@@H:13]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:14]1[OH:15])(=[O:11])[CH3:10]>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:15][C@H:14]1[S:16][CH2:17][C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:13]1[O:12][C:9](=[O:11])[CH3:10]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)SC[C@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reaction time: 4 h
Yield: 53 %

Procedure:
1.5 ml (15.10-3 mol) of trichloroacetonitrile and 70 mg of NaH (2.3.10-3 mol of NaH in 80% dispersion) are added to a solution of 1 g (3.42.10-3 mol) of 2, 3, 4 -tri-O-acetyl-5-thio-α-D-xylopyranose in 10 ml of methylene chloride. After 4 h at room temperature, the reaction medium is filtered on silica in methylene chloride and then purified by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 790 mg (yield: 53%) of the expected product are obtained after crystallization from an ethyl acetate/hexane mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2.COC1C=CC(C[NH:35][C:36]2[S:40][N:39]=[CH:38][N:37]=2)=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O)(C(F)(F)F)=O>CCOC(C)=O.[Cl-].[Na+].O.C(Cl)Cl.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([S:24]([NH:35][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:26])=[O:25])[CH:22]=[CH:23][C:14]1=2
Reactant: COc1ccc(CNc2ncns2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(S(=O)(=O)Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(S(=O)(=O)Nc3ncns3)ccc21
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a vial charged with 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (120 mg, 0.285 mmol) and N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (69.3 mg, 0.313 mmol) was added THF (948 μl) and the mixture cooled in a dry ice bath at −78 C. Then lithium bis(trimethylsilyl)amide (341 μl, 0.341 mmol) was added dropwise. The mixture was stirred at −78 C for 30 min, then warmed to 0 C for 30 min until conversion to the product by LCMS. The solution was added to ice, diluted with EtOAc (5 mL) and brine (5 mL) and extracted three times with EtOAc (3×5 mL). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. To the crude material was added DCM (1 ml) and TFA (548 μl, 7.11 mmol) and the mixture stirred at rt for 1 hr until deprotection occurred by LCMS. The mixture was concentrated and purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 m column with a gradient 5-95% acetonitrile and water with 0.1% TFA to give 4-(2-methoxy-4-(trifluoromethyl)phenyl)-3-oxo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (80 mg, 0.164 mmol, 57.0% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.81 (s, 3 H) 4.89 (s, 2 H) 6.38 (d, J=8.42 Hz, 1 H) 7.31 (dd, J=8.45, 1.86 Hz, 1 H) 7.36 (d, J=1.89 Hz, 1 H) 7.50 (d, J=8.08 Hz, 1 H) 7.55-7.62 (m, 2 H) 8.15 (s, 1 H). m/z ESI 485.0 (M−H)−.
Reaction SMILES: [OH:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:3]=[CH:4]/[C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].[CH:28](N=NNC1C=CC(C)=CC=1)([CH3:30])[CH3:29]>CC(C)=O>[CH:28]([O:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C@@H:5]1/[CH:4]=[CH:3]/[CH:2]([OH:1])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:30])[CH3:29]
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Reactant: Cc1ccc(NN=NC(C)C)cc1
Solvent: CC(C)=O
Product: CC(C)OC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A mixture of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (9.7 mg, 0.026 mmol), 1-isopropyl-3-p-tolyltriazene (5 mg, 0.028 mmol) and acetone (0.5 mL) was stirred at rt for 18 h. The reaction was quenched with saturated aqueous NH4Cl (2 mL) and extracted with CH2Cl2 (3×3 mL). The combined organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (50% CH2Cl2/Hexane→CH2Cl2→2% MeOH/CH2Cl2, gradient) afforded 5.1 mg (47%) of the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:11]([C:15]1[CH:20]=[C:19](Cl)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14].O>CN(C=O)C>[CH2:11]([C:15]1[CH:20]=[C:19]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: OCc1ccncc1
Reactant: C=CCCc1cc(Cl)n2nccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
60% sodium hydride, 0.55 g, was added to a 10 ml-solution of 1.6 g of 4-(hydroxymethyl)pyridine in DMF while being ice-cooled. After the mixture was stirred at 0° C. for 30 minutes, a DMF solution (2.5 ml) containing 2.6 g of 5-(3-butenyl)-7-chloropyrazolo[1,5-a]pyrimidine was added dropwise while being ice-cooled. The mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, water was added to the reaction mixture. The crystals precipitated were collected by filtration and washed with water and then with diethyl ether. The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to provide 1.5 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[C:17]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18].O>C(OCC)(=O)C.CC(C)=O.[Cu](Br)Br>[C:17]([CH:19]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])=[O:10])[C:20]([O:22][CH2:23][CH3:24])=[O:21])#[N:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1F
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(C#N)CC(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 124 %

Procedure:
To a solution of 2′-fluoroacetophenone (28.6 g) in ethyl acetate (400 mL), copper (II) bromide (92.6 g) was added, and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give crude 1-bromo-1-(2-fluorophenyl)ethanone (yield 90.5 g) as an oil. Potassium carbonate (88 g) was added to ethyl cyanoacetate (168 g), and the mixture was stirred at 45° C. for 1 hr. A solution (360 mL) of crude 1-bromo-1-(2-fluorophenyl)ethanone (90.5 g) in acetone was added dropwise over 20 min. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr. To the reaction mixture water (300 mL) and ethyl acetate (300 mL) were added, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium dihydrogenphosphate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. An excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→4:1) to give the title compound as an oil (yield 64.0 g, about 100%).
Reaction SMILES: C([Li])(CC)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[N:14]1[CH:19]=[C:18]2[C:20]([O:22][C:23](=[O:24])[C:17]2=[CH:16][N:15]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[C:20]([C:18]1[C:17]([C:23]([OH:24])=[O:22])=[CH:16][N:15]=[N:14][CH:19]=1)=[O:21]
Reactant: O=C1OC(=O)c2cnncc21
Reactant: Fc1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(O)c1cnncc1C(=O)c1cc(F)ccc1F
Temperature: -80 °C
Reaction time: 0.75 h
Yield: 61.3 %

Procedure:
Sec-butyllithium (1.32 M in cyclohexane; 1.25 mL) is added dropwise via syringe over 0.25 h to a stirred solution of 1,4-difluorobenzene (0.162 g) in tetrahydrofuran (THF) (5 mL) at -84° C. under a nitrogen atmosphere. The yellow mixture is stirred for an additional 45 min at -80° C. and then added via a canula over 5 min to a stirred solution of pyridazine 4,5-dicarboxylic acid anhydride (0.22 g; prepared according to J.Het Chem. 14, 1099, (1977)) in THF at -80° C. by nitrogen pressure. The mixture is warmed to room temperature overnight and neutralized with amonium chloride. After removal of THF at reduced pressure the resultant tan solid is treated with an aqueous sodium bicarbonate solution (10 mL) and washed with diethyl ether (10 mL). The aqueous phase is acidified with aqueous hydrochloric acid. The precipitate is collected by filtration, washed with cold water (3×10 mL) and dried to give 4-(2',5'-difluorobenzoyl)pyridazine-5-carboxylic acid (0.23 g) as an off-white solid, m.p. 202°-205° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH2:17][OH:18])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:20][N:21]([CH3:54])[C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:39]([C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:37])[O:27][CH2:28][C:29](O)=[O:30])=[O:23].CCN=C=NCCCN(C)C>CN(C)C1C=CN=CC=1.CC(C)=O>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:32]=[CH:33][C:34]([NH:35][C:36]([C:38]2[C:39]([C:44]3[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:51])[F:52])=[CH:46][CH:45]=3)=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37])=[C:24]([C:22](=[O:23])[N:21]([CH3:20])[CH3:54])[CH:25]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:19])[CH3:10]
Reactant: CN(C)C(=O)c1cc(OCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Product: CCOC(=O)C(COC(=O)COc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
4-Dimethylaminopyridine (53 mg), 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (116 mg) and {3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetic acid (176 mg) were dissolved in acetone (5 mL), and to the solution was added WSC (104 mg). The mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1) to give 2-(2-{3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenoxy}acetoxymethyl)-2-phenylmalonic acid diethyl ester (133 mg) as a colorless solid (m.p. 132-138° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.[CH3:21]S(O)(=O)=O.NC1C=CC=CC=1>>[NH2:20][C:8]([NH:4][C:5]1[CH:7]=[CH:21][CH:1]=[CH:2][CH:6]=1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Solvent: Nc1ccccc1
Product: Cc1ccc(S(=O)(=O)N=C(N)Nc2ccccc2)cc1

Procedure:
The compound of Example 5 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of aniline solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 289.35; found mol. wt. (M+H) 290.2; 579.0 (Dimer)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=[O:15].[CH3:17][CH2:18][C:19](=O)[CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:19]1([CH2:20][CH3:21])[N:2]([CH3:1])[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[C:14](=[O:15])[NH:16]1)[CH3:17]
Reactant: CCC(=O)CC
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)NC(=O)c2sc(-c3ccncc3)cc2N1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.094 g, 0.40 mmol), 3-pentanone (2.5 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 1.5 h at 150° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to 95:5 dichloromethane/methanol), then triturated with ethyl acetate/hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0281 g, 23%) as a yellow solid:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[C:27]([CH3:29])=[CH2:28].[C:36]([O:41][C:42]1(C)[CH2:47][CH2:46][Si](C)(C)CC1)(=[O:40])[C:37](C)=C>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10]([O:11][Si:12]([CH3:15])([CH3:13])[CH3:14])([O:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[C:27]([CH3:29])=[CH2:28].[C:1]([O:6][CH:7]1[CH:42]2[CH:47]3[CH:37]([CH2:9][CH:8]1[CH2:46]3)[C:36](=[O:40])[O:41]2)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OC1(C)CC[Si](C)(C)CC1
Agent: C=C(C)C(=O)OC(C)(C)C
Agent: C=C(C)C(=O)OCCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Product: C=C(C)C(=O)OC1C2CC3C(=O)OC1C3C2

Procedure:
A copolymer was synthesized as in Polymer Synthesis Example 1 except that 3-[tris(trimethylsilyloxy)silyl]propyl methacrylate and t-butyl methacrylate were used instead of 1,4,4-trimethyl-4-silacyclohexyl methacrylate. The polymer was confirmed by the light scattering method to have a weight average molecular weight of 13,000 g/mol and by the GPC elution curve to have a dispersity (Mw/Mn) of 1.78. By 1H-NMR analysis, the copolymer was found to contain the components in a ratio of approximately 2:5:3.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][Br:38].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: BrCCCCCCCCCCCBr
Reactant: C=CCCCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCCCCCBr)cc2)cc1
Yield: 183.6 %

Procedure:
A mixture of 2.80 g (8.68 mmol) of the compound obtained in Step 1, 8.18 g (26.0 mmol) of 1,11-Dibromo-undecane, 3.66 g ((26.0 mmol) of K2CO3 and 40 mL of dry butanone is refluxed for 24 h, then the reaction mixture is allowed to return to room temperature. The mixture is filtered and the solvent is distilled off under reduced pressure. The resulting crude is purified by column chromatography on silica gel using CH2Cl2 as eluent to give a pure white solid (9.11 g, 41% yield).
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH:21]=[CH:22][NH:23]3)=[CH:19][CH:18]=2)=[O:16])=[CH:10][C:9]=1[Cl:26].[OH-].[NH4+]>C(O)(=O)C.O.ClCCl>[CH3:5][O:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][CH2:22][NH:23]3)=[CH:19][CH:18]=2)=[O:16])=[CH:10][C:9]=1[Cl:26]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1Cl
Agent: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium cyanoborohydride (2.6 g, 41.6 mmol, 3 equiv.) was added to a stirred solution of 2-chloro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester (1.4 g, 4.2 mmol, 1 equiv.) in acetic acid (25 mL) over 5 minutes at room temperature. The mixture was stirred for 30 minutes then cooled to 0° C. and poured onto concentrated ammonium hydroxide (78 mL, d=0.880) at 0° C. The mixture was diluted with water (25 mL) and dichloromethane (25 mL), the organic layer was separated and the aqueous layer extracted with dichloromethane (2×25 mL). The combined organic layers were dried over Na2SO4 and the solvent removed under vacuum to afford crude 2-chloro-4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester, 0.75 g, this material was taken onto the next step without further purification. LC @215 nm; Rt 1.04: 71%, m/z (ES+): 331 (M+H+.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH:5]=1.[CH:22]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(=O)OCC>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7](/[CH:23]=[CH:22]/[S:24]([CH3:27])(=[O:26])=[O:25])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(/C=C/S(C)(=O)=O)c(OCCc2cccc(C)c2)c1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
500 mg of 4-Iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester, 200 mg of methyl vinyl sulfone, 115 mg of tri-o-tolylphosphine, and 43 mg of palladium(II) acetate were stirred in 4 ml of acetonitrile and 1.5 ml of diisopropylethylamin for 2 h at 82° C. The reaction mixture was allowed to cool to room temperature. 10 ml of EA were then added and the mixture was washed successively twice using 5 ml of water each and twice using 5 ml of a saturated aqueous Na2CO3-solution. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 270 mg of the title compound. Rf (EA/HEP 1:2)=0.17
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([CH2:14][CH2:15][C:16](Cl)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C(C)C(O)=O)C=CC=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]1([CH2:14][CH2:15][C:16]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: OC1CCNCC1
Agent: CC(C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCc1ccccc1)N1CCC(O)CC1
Reaction time: 24 h
Yield: 38.9 %

Procedure:
This amine was synthesized in accordance with the method of Scheme 37. To 4 g (40 mmol) of 4-hydroxypiperidine in 20 mL of toluene was added phenylpropionyl chloride (derived from 6 g (40 mmol) of phenylpropionic acid in excess thionyl chloride). To the mixture was added excess 2N aqueous NaOH. After stirring 24 hours, the toluene layer was discarded and the aqueous phase was extracted with CH2Cl2, dried, and evaporated under vacuum to give 3.63 g (39%) of 1-(3-phenylpropionyl)-4-hydroxypiperidine (134). GC/MS indicated 100% purity with a molecular ion of 233.