Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[CH:37][C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19].O>CN(C=O)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[C:33]4[C:34]([NH2:38])=[N:35][CH:36]=[C:37]([I:8])[C:32]=4[O:31][CH:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21]1)=[O:19]
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(I)c2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A solution of NIS (147 mg, 0.653 mmol) in DMF (3 mL) was added dropwise to a solution of 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (257 mg, 0.634 mmol) in DMF (3.5 mL) at −40° C., and the mixture was stirred and allowed to slowly warm to room temperature (temperature was still <−10° C. after 2 hours, and reaction had progressed to about 20% according to HPLC). After 18 hours HPLC indicated complete consumption of starting material, and only a small amount of diiodo byproduct had formed. The reaction mixture was poured into water (35 mL), stirred for about 10 minutes, and the precipitate was collected by vacuum filtration and dried by suction for several hours to give 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-iodofuro[3,2-c]pyridin-4-amine (253 mg) as a tan solid. LC/MS (ES) m/z=532 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH3:15][N:16]([CH3:33])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[CH3:15][N:16]([CH3:33])[C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[C:12]([CH:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH2:6][CH2:7][CH2:8]2)=[O:14])=[CH:21][CH:22]=1
Reactant: O=C(O)C1CCCc2ccc(F)cc21
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(F)cc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](4-methoxyphenyl)amine (0.54 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This compound was dissolved in ethyl acetate, and 4 mol/L-HCl/dioxane was added. The precipitated solid was collected by filtration to give N-[(4-dimethylaminophenyl)methyl]-7-fluoro-N-(4-methoxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ hydrate (0.52 g). melting point: 125.4° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.[H-].[Na+].[I-].[Na+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:22][CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:19]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COCCc1cc2ccccc2n1-c1ccc(O)cc1
Reactant: ClCCCN1CCCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCc1cc2ccccc2n1-c1ccc(OCCCN2CCCC2)cc1
Temperature: 70 °C
Yield: 47.4 %

Procedure:
4-[2-(2-Methoxyethyl)indol-1-yl]phenol (0.39 mmol) was dissolved in N,N-dimethylformamide (4 mL), and 1-(3-chloropropyl)pyrrolidine (58 mg, 0.39 mmol), sodium hydride (19 mg, 60% dispersion in mineral oil, 0.47 mmol), and sodium iodide (59 mg, 0.39 mmol) were added. The reaction was heated at 70° C. for 1.5 hours, then carefully quenched with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography to give 70 mg of the desired product. LC-MS (C24H30N2O2 calc'd 378) m/z 379 (M+H); 1H NMR (300 MHz, CDCl3) d 7.60-7.56 (m, 1H), 7.25-7.21 (m, 2H), 7.10-7.00 (m, 5H), 6.45 (s, 1H), 4.11 (t, J=6.3 Hz, 2H), 3.57 (t, J=7.2 Hz, 2H), 3.30 (s, 3H), 2.89 (t, J=7.2 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.65 (m, 4H), 2.16-2.05 (m, 2H), 1.90-1.81 (m, 4H).
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1O
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1F
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A well stirred suspension of 3.0 g (0.01 mole) of 3-hydroxy-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 150 ml of methylene chloride was cooled to -70°, and 7.5 ml (0.06 mol) of diethylaminosulfur trifluoride was added dropwise over a period of 10 min. The reaction mixture was then allowed to warm slowly over a period of 26 min. to -10° and then poured into 200 ml of ice water. The organic layer was separated, dried over MgSO4, and evaporated to dryness under reduced pressure to give 2.95 g (98%) of crude product. Recrystallization from benzene-heptane gave 2.00 g (67%) of 3-fluoro-1,3-dihydro-7-chloro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one as off-white crystals: mp 206°-207° (dec); 1H nmr (DMSO-d6) δ 5.95 ppm (d, J = 56 Hz, 1H), 7.47 ppm (m, 7H), 11.25 ppm (s, 1H); 19F nmr (DMSO-d6) δ -162.0 ppm (d, J = 56 Hz, 1F) and δ -113.0 ppm (m, 1F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:22]([NH:28][S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CCCCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCNS(=O)(=O)c1ccc(OC)c(OC)c1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of 3,4-dimethoxybenzenesulfonyl chloride (0.500 g, 2.11 mmol), triethylamine (0.750 mL, 5.30 mmol) in 7 mL of ethyl acetate, hexylamine (0.280 mL, 2.11 mmol) was added dropwise and the resulting solution was stirred overnight. The reaction mixture was filtered and the filtrate was washed 1N HCl (2×), dried with MgSO4, filtered and concentrated in vacuo to afford 0.480 g (75%) of N-hexyl-3,4-dimethoxybenzenesulfonamide as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.46 (m, 1H), 7.32 (m, 1H), 6.94 (m, 1H), 4.22 (m, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 2.93 (q, J=6.4 Hz, 2H), 1.44 (quintet, J=6.9 Hz, 2H), 1.25 (m, 6H), 0.84 (t, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.Cl>O1CCCC1>[F:1][C:2]([F:12])([F:13])[C@@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][OH:10])[CH2:7][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@@H](C(F)(F)F)CC1
Agent: Cl
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
cis-4-(Trifluoromethyl)cyclohexanecarboxylic acid (1.05 g, 5.4 mmol) and tetrahydrofuran (20 ml) were mixed and ice-cooled. A borane-tetrahydrofuran complex (10.71 ml, 10.7 mmol) was added to the mixture dropwise. After the completion of dropwise addition, the reaction mixture was stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to afford the title compound as a colorless oil (0.92 g, 94%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34]([OH:36])=O)=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[CH2:54]([NH:56][CH2:57][CH2:58][N:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[CH3:55].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:54]([N:56]([CH2:57][CH2:58][N:59]1[CH2:60][CH2:61][O:62][CH2:63][CH2:64]1)[C:34](=[O:36])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:43])([F:44])[F:1])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)=[O:30])[CH:32]=1)[CH3:55]
Reactant: CCNCCN1CCOCC1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 25 mg of 3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid 4.1e, 17 mg of diisopropylethylamine and 9 mg of N-ethyl-2-morpholinoethanamine in 1 mL of DMF was added 17 mg of HATU. The mixture was stirred at 25° C. for 1 h. The solution was injected onto a preparative reverse phase HPLC and the product was eluted with 0.5% TFA in a gradient of water and acetonitrile. The yield was 11.2 mg of product. 1H-NMR (400 MHz, DMSO-d6, ppm) δ 12.46 (s, 1H), 9.90 (s, 1H), 9.57 (t, J=6.1 Hz, 1H), 8.90 (d, J=5.1 Hz, 1H), 8.36, (s, 2H), 8.03-7.92 (m, 2H), 7.87 (dd, J=5.1, 1.3 Hz, 1H), 7.75-7.53 (m, 26H), 7.39 (s, 1H), 4.63 (d, J=5.8 Hz, 2H), 4.03 (s, 2H), 3.82 (s, 2H), 3.60 (s, 4H), 3.40 (d, J=23.1 Hz, 6H), 3.24 (s, 4H), 1.77 (s, 4H), 1.61 (s, 2H), 1.08 (t, J=6.5 Hz, 10H). MS (ES, m/z): 743 [M+H]+.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc[n+]([O-])c1
Solvent: CCN(CC)CC
Product: O=C(O)c1cccnc1Cl
Temperature: 100 °C

Procedure:
70 gm. of nicotinic acid-N-oxide was suspended in 300 ml of POCl3. Then 50 gm. of triethyl amine was added drop by drop at room temperature, whereby the nicotinic acid-N-oxide dissolved at about 50° C. (the temperature rise occured due to an exothermic reaction). Then the solution was heated in a water bath at 100° C. for another 4 hours. The main quantity of excess phosphorus oxychloride was distilled off under vacuum. The residue was allowed to flow into water at a temperature below 40° C. After addition of diluted caustic soda solution, the 2-chloronicotnic acid precipitated at a pH value of 2.0 to 2.5. The product had a melting point of 173° to 175° C. (Kofler). The product (2-chloronicotinic acid) yield amounted to 65 to 70 percent of theory.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]([F:8])([F:7])[F:6].C(=O)([O-])[O-].[Na+].[Na+].[CH3:15][O:16][CH2:17][C:18]1[S:22][C:21]2=[N:23][C:24]([C:28]([F:31])([F:30])[F:29])=[C:25]([CH2:26][NH2:27])[N:20]2[N:19]=1>CN(C)C=O>[F:6][C:5]([F:8])([F:7])[CH:4]=[CH:3][CH2:2][NH:27][CH2:26][C:25]1[N:20]2[C:21]([S:22][C:18]([CH2:17][O:16][CH3:15])=[N:19]2)=[N:23][C:24]=1[C:28]([F:29])([F:31])[F:30]
Reactant: FC(F)(F)C=CCBr
Reactant: COCc1nn2c(CN)c(C(F)(F)F)nc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1nn2c(CNCC=CC(F)(F)F)c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-bromo-1,1,1-trifluorobut-2-ene (0.782 g, 4.14 mmol, 1.4 eq) and sodium carbonate (0.376 g, 3.55 mmol, 1.2 eq) are added to suspension of 1-[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanamine a19 in N,N-dimethylformamide (15 ml). The mixture is stirred overnight at room temperature to afford crude 4,4,4-trifluoro-N-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}but-2-en-1-amine a20. Ethoxycarbonyl isocyanate (0.51 g, 4.43 mmol, 1.5 eq) is added to the reaction mixture. After 4 h, the reaction is not complete and ethoxycarbonyl isocyanate (0.5 eq) is added again. The reaction mixture is stirred overnight to afford crude ethyl ({[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}[(4,4,4-trifluorobut-2-en-1-yl]carbamoyl)carbamate a21. Potassium tert-butoxide is added and the reaction mixture is heated at 75° C. for 4 h. After cooling, the reaction mixture is extracted with toluene (2×80 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by chromatography over silicagel (eluent: CH2Cl2/MeOH 99/1) to afford 602 mg of a mixture of ethyl 5-(2,2-difluoroethenyl)-3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxoimidazolidine-1-carboxylate a22 (as the major compound) and ethyl 3-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-2-oxo-5-(2,2,2-trifluoroethyl)imidazolidine-1-carboxylate a23.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[CH3:16][C:17](=O)[CH2:18][CH2:19][C:20](=O)[CH3:21]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([N:8]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:16])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: CN1CCN(c2c(N)cncc2Br)CC1
Reactant: CC(=O)CCC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1cncc(Br)c1N1CCN(C)CC1

Procedure:
5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine (3000 mg, 11.06 mmol), hexane-2,5-dione (6.312 g, 6.487 mL, 55.30 mmol) in acetic acid (20 mL) was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and an aqueous saturated solution of NaHCO3. Combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo yielding an oil that was purified by filtration on silica to yield 1-(3-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-4-yl)-4-methylpiperazine as an off-white solid. MS (ES+) 351.1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23].[OH-].[Na+]>CS(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][O:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]#[N:23]
Reactant: ClCc1ccc2ccccc2n1
Reactant: N#CCCCOc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CCCCOc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 66.3 %

Procedure:
A mixture of 15.3 g of 2-chloromethylquinoline hydrochloride, 12.6 g of 4-(3-hydroxyphenoxy)butyronitrile and 5.7 g of sodium hydroxide was stirred with 80 ml of dimethylsulfoxide at room temperature for 4 hours. The reaction mixture was partitioned between water and ether. The ether extract was evaporated to yield 23.9 g, of crude product. Crystallization from ethyl acetate:hexane and then from ethanol:hexane gave 15 g of grey needles, m.p. 84°-85° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C([Li])CCC.CCCCCC.[CH:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1.CCOCC>[OH:33][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccccc1CC(O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 58 %

Procedure:
A stirred solution of N-[(2-methyl)phenyl]-2,2-dimethyl-propanamide (95.6 g, 0.5 mol) in THF (500 ml) was cooled to 0° C. and treated with 1.6M n-butyllithium in hexane (628 ml, 0.1 mol). The addition of n-butyllithium was complete after 45 minutes. During the addition, the temperature of the mixture was maintained below 10° C. with external cooling. The resultant dianion solution was aged for 2 hours at 0° C. until the homogeneous orange solution became a yellow heterogeneous slurry. The dianion was then quenched with benzaldehyde (63.6 g, 0.6 mol) and aged for 15 minutes at about 24° C. The reaction mixture was diluted with ether (200 ml), treated with crushed ice (200 g), and stirred for 5 minutes. The organic phase was separated, washed with saturated sodium chloride (250 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residual oil was crystallized from hexane, filtered and recrystallized from dichloromethane (500 ml reflux) to give N-[2-(2-hydroxy-2-phenylethyl)-phenyl]-2,2-dimethylpropanamide (87 g, 0.29 mol) in 58% yield. The product had a melting point of 183°-184° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH2:7]2.[CH:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=[CH2:23].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].C(Cl)(Cl)Cl.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:7][C:6]3[C:10](=[C:2]([CH:23]=[CH:22][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH:3]=[CH:4][CH:5]=3)[C:9]2=[O:11])=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: C=Cc1ccncc1
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(Br)c3C2=O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(N2Cc3cccc(C=Cc4ccncc4)c3C2=O)cc1
Reaction time: 0.17 h

Procedure:
7-Bromo-2-(4-t-butyl-phenyl)-2,3-dihydro-isoindol-1-one (0.14 g), 4-vinylpyridine (0.55 mL), Pd(OAc)2 (1.2 mg), tri-o-tolylphosphine (27.3 mg), and 2 mL of Et3N were added into a microwave reaction tube and subjected to 120° C., 10 min of microwave (2×). H2O and CHCl3 were added and the layers were separated. The aqueous phase was extracted with CHCl3 (3×). The combined organic phases were washed with H2O, dried over Na2SO4, filtered, then evaporated in vacuo to yield a light brown residue as crude product. The crude was purified by silica gel chromatography (25 g, 10-50% EtOAc/hexanes) to afford 2-(4-t-butylphenyl)-7-(2-pyridin-4-yl-vinyl)-2,3-dihydro-isoindol-1-one as an off-white solid:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]=1.C(Cl)Cl.O(OC(C)=O)[O:26][C:27]([CH3:29])=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CO>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:27](=[O:26])[CH3:29])=[CH:17][CH:18]=2)[CH2:9][CH2:10][CH:11]=1
Reactant: CC(=O)OOOC(C)=O
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(N)cc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCC1=CCCN(Cc2ccc(NC(C)=O)cc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 229.4 %

Procedure:
17.5 mg of 3-[1-(4-amino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid methyl ester (h) prepared by above Step 1 was dissolved in methylene chloride solution (0.06 mmol). And then 6 μl of (AcO)2O (0.07 mmol), 0.01 ml of triethylamine (0.08 mmol) and 1.0 mg of DMAP (0.008 mmol) were added thereto and the mixture was stirred for 3 hrs at 0° C. The reaction was stopped by adding methanol and the mixture was extracted three times with 10 ml of ethyl acetate. The organic layer was washed with saturated NaCl solution, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified with Silica gel column chromatography with ethylacetate as an eluant to give 46 mg of 3-[1-(4-acetylamino-benzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-propionic acid methyl ester (i) (yield: 44%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl>[CH2:28]([O:27][C:25]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Yield: 96.7 %

Procedure:
To a solution of 1.2 g (6.0 mmol) 4-amino-1-(tert-butoxycarbonyl)piperidine from Step B in 40 mL of dichloromethane was added 3.15 mL (18 mmol) of N,N-diisopropylethylamine and 1.03 mL (7.2 mmol) of benzyl chloroformate while cooled in an ice bath. After 0.5 h the reaction was quenched with aqueous sodium carbonate and extracted three times with dichloromethane. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by flash column chromatography, eluting with 25% ethyl acetate in hexane, to afford 1.94 g of title compound. 1H NMR (400 MHz, CDCl3): δ 7.33 (m, 5H), 5.09 (s, 2H), 4.42 (bs, 1H), 4.08 (m, 2H), 3.58 (m, 1H), 2.90 (bt, 2H), 1.90 (bd, 2H, J=12 Hz), 1.42 (s, 9H), 1.26 (m, 2H).
Reaction SMILES: [SH2:1].[C:2]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:3].C(N(CC)CC)C.Cl>N1C=CC=CC=1>[CH2:9]([O:8][C:6]([CH2:5][CH2:4][C:2]([NH2:3])=[S:1])=[O:7])[CH3:10]
Reactant: S
Reactant: CCOC(=O)CCC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)CCC(N)=S
Reaction time: 8 h

Procedure:
Hydrogen sulfide was introduced with stirring at room temperature into a solution of 31.8 g (0.25 mol) of ethyl 3-cyanopropionate and 34.6 ml (0.25 mol) of triethylamine in 75 ml of pyridine for 9 hours. After allowing to stand overnight, the reaction mixture is rendered acidic with 2N hydrochloric acid with cooling and extracted several times with ethyl acetate. The combined organic phase, which is dried over sodium sulfate, is carefully concentrated under reduced pressure. The oily residue remaining (35.0 g =87 % of theory) is composed of about 87 % of 3-(ethoxycarbonyl)thiopropionamide and 13 % of ethyl 3-cyanopropionate according to GC analysis.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:13])[CH:11]=[CH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CC(=O)N(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 2 liter 3-necked flask were combined 129 g (1 mol) di-(n-butyl)amine (Fisher Scientific) and 0.5 l dry toluene and cooled to 5° C. 46 g (0.5 mol) acryloyl chloride dissolved in 50 ml toluene were added slowly so the temperature remained below 10° C. After the addition the flask was warmed to 25° C. and the precipitate removed by filtration. 1 g DNPD was added, and after concentration on a rotary evaporator the product was distilled at 20 torr and 61°-63° C. Yield 77 g (84%).