Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2].[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([Cl:37])=[CH:39][CH:40]=3)=[CH:17][C:16]=2[CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24][CH3:25])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN(CC)C(=O)OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3ccc(Cl)cc3)cc2CN(CC)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3-{4-Amino-2-[(benzyloxycarbonyl-ethyl-amino)-methyl]-phenoxy}-4-methoxy-phenyl)-acetic acid ethyl ester (0.1 g, 0.19 mmol), 4-chlorobenzoyl chloride (0.1 g, 0.57 mmol), and triethylamine (0.5 mL, 3.6 mmol) were combined in CH2Cl2 (10 mL) and stirred at room temperature for 20 minutes. The mixture was concentrated to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Si:26]([O:1][CH2:2][C@@H:3]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:7][CH:6]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1N[C@H](CO)Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H](Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 40 °C
Reaction time: 60 h
Yield: 68.9 %

Procedure:
4-{(2S)-3-Hydroxy-2-[(3-nitroquinolin-4-yl)amino]propyl}phenol (21.69 g, 64.5 mmol) was dissolved in 100 mL of dry pyridine and treated with tert-butyldimethylsilyl chloride (22.4 g, 148 mmol) and a catalytic amount of DMAP (0.79 g, 6.45 mmol). The reaction mixture was stirred under N2 and heated to 40° C. After 2.5 days, the reaction mixture was concentrated under reduced pressure. The resulting orange residue was partitioned between 200 mL of ethyl acetate and 200 mL of H2O. The layers were separated and the organic portion was washed sequentially with H2O and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(4-{[tert-butyl(dimethyl)silyl]oxy}benzyl)ethyl]-3-nitroquinolin-4-amine (25.24 g) as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[C:23]=4[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CN1CCC(O)CC1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2C2CCN(C)CC2)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60 and 1-methyl-piperidin-4-ol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].O>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[CH2:24][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)c1cccc(CCN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CNCCc1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 3-(2-aminoethyl)benzoate (900 mg) in N,N-dimethylformamide (20.0 mL) were added potassium carbonate (600 mg) and tert-butyl bromoacetate (0.600 mL) under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{2-[(2-tert-butoxy-2-oxoethyl)amino]ethyl}benzoate (738 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: COC(=O)c1ccccc1C(C)Br
Reactant: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 3-chlorophenol (8.2 g) in DMF (30 ml) was added dropwise to a stirred suspension of sodium hydride (1.3 g) in DMF (30 ml). An hour later, a solution of crude methyl 2-(1-bromoethyl)benzoate described above (12 g) in DMF was added with stirring. After stirring at room temperature for 2 hours, the resulting mixture was poured into water and extracted with ether. The ether extracts were washed successively with water (×2), aqueous sodium hydroxide (×2), and brine, then dried and concentrated to give methyl 2-[1-(3-chlorophenoxy)ethyl]-benzoate (14.84 g, 88% pure by GC), as a yellow oil.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][CH3:9].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[CH2:1]([OH:10])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH3:9]
Reactant: CCC#CCC#CCCO
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC/C=C\C/C=C\CCO

Procedure:
(3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate can be prepared from 2-Pentyn-1-ol by dissolving 2-Pentyn-1-ol (1.03 g, 12 mmol) in chloroform (10 ml) and adding pyridine (1.90 g, 24 mmol) followed by p-toluenesulfonyl chloride (3.43 g, 18 mmol) in small portions with constant stirring. After about 4 hrs, ether (30 ml) and water (7 ml) can be added and the organic layer can be washed successively with HCl (7 ml), 5% NaHCO3, water (7 ml) to produce pent-2-ynyl p-toluenesolfonate. Pent-2-ynyl p-toluenesolfonate (1.37 g, 5.78 mmol, 1.1 eq) can be added at low temperature under nitrogen to a well-stirred suspension in DMF (15 ml) of but-3-yn-1-ol (368 mg, 5.25 mmol), sodium carbonate (834 mg, 7.87 mmol), tetrabutylammonium chloride (1.46 g, 5.25 mmol) and copper(I) iodide (1.00 g, 5.25 mmol). The mixture can then be stirred at room temperature for about 48 hrs, and ether (30 ml) and 1M HCl (30 ml) can be added, the organic phase can be collected and washed with brine, and dried over sodium sulfate to produce nona-3,6-diyn-1-ol. Nona-3,6-diyn-1-ol (198 mg, 1.45 mmol) can be hydrogenated at atmospheric pressure, in the presence of a mixture of quinoline (44 mg) and palladium (5%) on calcium carbonate (100 mg), poisoned with lead in methanol (25 ml). After several hours, the methanol can be evaporated in vacuo, quinoline can be removed by silica gel column chromatography using ether-hexane (35:65) as the eluent to produce (3Z,6Z)-nona-3,6-dien-1-ol. (3Z,6Z)-Nona-3,6-dien-1-ol (167 mg, 1.19 mmol) can be dissolved in chloroform (5 ml) and the solution can be cooled in an ice bath. Pyridine (376 mg, 4.76 mmol) can be added, followed by p-toluenesulfonyl chloride (340 mg, 1.78 mmol) in small portions with constant stirring. The mixture can be stirred for about 24 hrs at low temperature, and ether (15 ml) and water (5 ml) can be added, the organic layer can be collected and washed successively with 1 N HCl (10 ml), 5% NaHCO3, water (10 ml), and brine (10 ml), and then dried over Na2SO4 to produce (3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])([CH3:36])[CH3:35]>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[C:7]1[CH:13]=[CH:14][C:4]([C:1]2[O:3][C:45](=[O:46])[C:44]([S:43][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:34]([CH3:35])[CH3:36])=[C:48]([OH:49])[CH:2]=2)=[CH:5][CH:6]=1)[CH3:12]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(O)c(Sc3ccccc3C(C)C)c(=O)o2)cc1

Procedure:
The title compound was prepared by Method A using ethyl 4-acetylbenzoate (2.93 g, 15.1 mmol), trimethylsilyl triflate (3.5 mL, 18.1 mmol), triethylamine (4.26 mL, 30.6 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio]propanedioic acid (3.11 g, 10.0 mmol) m.p. 201-203° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 1.35 (t, 3H), 3.42 (m, 1H), 4.35 (q, 2H), 6.94 (m, 1H), 7.00 (s, 1H), 7.10 (m, 2H), 7.28 (m, 1H), 7.99 (m, 2H), 8.11 (m, 2H).
Reaction SMILES: O1CC1CO[C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].C1(CN)CCCCC1>C(O)C>[NH:15]1[C:16]2[C:12](=[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:19]=[CH:18][CH:17]=2)[CH:13]=[CH:14]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Agent: NCC1CCCCC1
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1

Procedure:
A solution of 2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 50 ml of ethanol in the presence of 1.147 g of cyclohexane methylamine was refluxed for 2 hours and 15 minutes and the solvent was evaporated under reduced pressure. The residue was chromatographed over silica (eluent: methylene chloride-methanol, 9-1) to obtain 1.97 g of 2-[3-(cyclohexylmethyl)amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide.
Reaction SMILES: FC(F)(F)[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:36])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[F:35])[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[CH:3][N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2ccnc2C1)Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol), HOBT (26.9 mg,0.199) mmol, and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) gave 40 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H) 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H), 4.97-5.48 (m, 2H) 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[N:12]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1COCC1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][S:28]([CH3:27])(=[O:30])=[O:29])[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CCCCc1nc(-c2ccccc2N)co1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)CCCCc1nc(-c2ccccc2NS(C)(=O)=O)co1
Temperature: 25 °C

Procedure:
Dissolve 5-[4-(2-amino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.18 g, 7.96 mmol) in THF (50 mL) and add pyridine (1.20 mL, 14.8 mmol). Add methanesulfonyl chloride (excess) and allow the mixture to stir at room temperature until reaction is complete. Concentrate the mixture and quench the residue with ice/aq NaHCO3 and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the residue over silica gel (EtOAc/CH2Cl2) to allow for isolation of 5-[4-(2-methanesulfonylamino-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (2.8 g, 100%). MS (ES): (M+1)+ 353.2, 354.3 m/z.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>O>[OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:21][OH:22])[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 75 °C

Procedure:
4,4'-dihydroxybenzophenone (100.0 grams, 0.467 mole) is added to ethanol (300 milliliters) in a 1 liter Erlenmeyer flask and stirred. After dissolution of the 4,4'-dihydroxybenzophenone, a solution of hydroxylamine hydrochloride (48.6 grams, 0.699 mole) and sodium acetate (57.4 grams, 0.700 mole) in deionized water (70 milliliters) is added followed by an additional 100 milliliters of ethanol. This mixture is stirred and heated on a hot plate to a gentle reflux (75° C.). After heating for 4 hours, the solution is allowed to cool to room temperature (25° C.) with stirring and then filtered. The filter cake is washed with ethanol (100 milliliters); then the total filtrant obtained (600.4 grams) is concentrated to a weight of 219.2 grams by evaporation of the ethanol and water. The concentrated solution is placed into a 1 liter Erlenmeyer flask then stirred as 600 milliliters of deionized water is added. The addition of the deionized water induced formation of a white precipitate. After thirty minutes of stirring, the mixture is filtered. The solid 4,4'-dihydroxybenzophenone oxime thus obtained weighed 98.22 grams after drying. 4,4'-Dihydroxybenzophenone oxime (66.0 grams, 0.288 mole) and glacial acetic acid (330 milliliters) are added to a 500 milliliter round bottom flask equipped with a stirrer, water cooled condensor, nitrogen purge and heating mantle. A catalytic amount of p-toluenesulfonic acid (1.85 grams, 0.027 mole) is added and the reaction mixture then heated to 83° C. After heating for approximately two hours, a precipitate formed and the mixture is stirred for an additional two hours at 87° C. After this time, 25 milliliters of deionized water is added to the reactor and after thirty minutes, the contents of the reactor is transferred to a 1 liter Erlenmeyer flask and maintained therein with stirring. Immediately following the transfer, 400 milliliters of deionized water is added to the flask. The mixture is stirred for forty five minutes and then filtered. The filter cake thus obtained is washed with 800 milliliters of deionized water and then dried. The resultant light beige colored solid weighed 54.82 grams. Fourier transform infrared spectrophotometric analysis of a portion of the product confirmed the product structure as that of 4,4'-dihydroxybenzanilide. Differential scanning calorimetry demonstrated a sharp melting point endotherm at 273° C. for the 4,4'-dihydroxybenzanilide product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:30]([C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=1)(=[O:31])=[O:32]
Reactant: COC(=O)[C@@H](CCCCN)Nc1cc(C)c(F)c(C)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of (R)-6-amino-2-(4-fluoro-3,5-dimethyl-phenylamino)-hexanoic acid methyl ester (0.200 g, 0.709 mmol) and 3-nitro-benzenesulfonyl chloride (0.157 g, 0.709 mmol) in 10 mL of dichloromethane, was added triethylamine (0.5 mL, 3.544 mmol). After stirring at room temperature under N2 for 16 h, the reaction mixture was concentrated under reduced pressure. The product was isolated by Flash chromatography (silica gel) eluting with 20-50% ethyl acetate/hexanes to give the title compound as light yellow semi-solid (0.128 g, 39% yield). LC-MS: tR=9.5 min; m/z 468 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[S:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CC2SC(=S)NC2=O)cc(C(C)(C)C)c1O
Yield: 56.9 %

Procedure:
Under a nitrogen atmosphere, 13.98 g of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene}-2-thioxo-4-thiazolidinone, 13.17 g of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate and 600 ml of toluene were stirred to effect solution. Forty grams of silica gel 60 (finer than 230 mesh) previously dried in vacuo at 50° C. for 7 hours were added to the reaction. The reaction was heated at reflux for 18 hours and filtered hot. The filtrate was evaporated to dryness. The residue was dissolved in 500 ml of ethyl acetate, washed 5 times each with 400 ml of 1N hydrochloric acid, dried over sodium sulfate, filtered, and evaporated in vacuo to provide a yellow solid. Chromatography over silica gel eluting with 2.5% ethyl acetate in toluene provided 8.0 g of the desired title product, m.p. 178-179° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:32])[CH3:31])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:36]C(=O)C>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][N:25]([CH:30]([CH3:31])[CH2:32][CH3:36])[CH2:24]5)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CN(C(C)C)C5)cc23)CC1
Reactant: CC(C)=O
Product: CCC(C)N1Cc2ccc(-c3cc(C(N)=O)c4[nH]cc(C5CCN(S(=O)(=O)CC)CC5)c4c3)cc2C1

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1H-isoindol-5-yl]-1H-indole-7-carboxamide, substituting 2-butanone (14 mg, 0.198 mmol) for 2-propanone to afford 14.6 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:42]1[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=1[Cl:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from example 143 step 12 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:12][CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[C:5]1([C:3]2[N:17]=[C:15]([NH:14][CH2:11][CH2:12][CH3:13])[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCNC(N)=S
Reactant: O=C(CCl)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCNc1nc(-c2ccccc2)cs1
Yield: 89.7 %

Procedure:
To a solution of 2-chloroacetophenone (4.45 g, 28.8 mmol) and N-propylthiourea (3.40 g, 28.8 mmol) in ethanol (50 mL) was added sodium acetate (3.07 g, 37.4 mmol), and the mixture was heated under reflux for 1.5 hrs. Water was added to the reaction mixture, and crystals were collected by filtration. The obtained crude crystals were recrystallized from diethyl ether-hexane to give the title compound (5.64 g, 92%) as colorless crystals.
Reaction SMILES: [OH-:1].[K+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.O>O>[CH:6]12[CH2:7][CH:4]([CH:4]=[CH:5]1)[CH2:5][CH:6]2[C:7]([OH:3])=[O:1]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: O=C(O)C1CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
67.0 g (269 mmol) of the Diels-Alder adduct was dissolved in 1040 ml of a mixture solvent of tetrahydrofuran-water (5:2), 70.5 g (1.08 mol) of potassium hydroxide (85%) in 300 ml of water was added on ice cooling, and the mixture was stirred at room temperature for 24 hours. After distilling out tetrahydrofuran, the product was neutralized with 94 ml of concentrated hydrochloric acid and extracted with a mixture solvent of hexane-methylene chloride (98:2) (200 ml×4). The extract was dried on anhydrous magnesium sulfate, the solution was filtered, and the solvent was distilled off to obtain 38.8 g of crude 5-norbornene-2-carboxylic acid. Crude yield: 100%.