Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.O([O+](OCC)OCC)CC.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH2:21][NH:22][C:23](=O)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32].Cl.[C:35]1([C:41]2([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:49]3[C@H:45]([CH2:46][NH:47][CH2:48]3)[C:44](=[O:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.C(N(CC)CC)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][C:23]([N:47]1[CH2:46][C@H:45]2[C@H:49]([C:41]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:42][CH2:43][C:44]2=[O:50])[CH2:48]1)=[N:22][CH2:21][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccccc1CC(=O)NCc1cccs1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: CCO[O+](OCC)OCC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=NCc1cccs1)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reaction time: 7 h
Yield: 25.3 %

Procedure:
Triethoxyloxonium tetrafluoroborate (4 g) is added to a stirred solution of N-(2-thienyl)methyl-2-(2-methoxyphenyl)acetamide (5.2 g) in anhydrous dichloromethane (50 cc). Stirring of the reaction mixture is continued for 7 hours, at ambient temperature. The mixture is cooled to +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (4.6 g) and triethylamine (5 cc) in dichloromethane (50 cc) is then added. Stirring of the reaction mixture is then continued for 20 hours at ambient temperature and the reaction mixture is then refluxed for 1 hour. It is then treated, after the temperature has returned to ambient temperature, with a 10% aqueous potassium carbonate solution (100 cc); the organic phase is washed with distilled water (40 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Pechiney CBT1 neutral alumina gel column (diameter 5 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 100 cc fractions. Fractions 4 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropanol (20 cc); the crystals obtained are drained, washed with isopropyl ether (10 cc) and dried. (3aR,7aR)-2-[2-(2-methoxyphenyl)-1-(2-thienylmethyl)iminoethyl]-7,7-diphenyl-4-perhydroisoindolone (1.9 g) melting at 88° C. is obtained; [α]D20 =-170° (c=1, methanol).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5]1)[CH2:2][CH3:3].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=[C:6]2[CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[CH3:26])[CH3:22]
Reactant: CCCn1cc(Cc2ccncc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1cc(Cc2ccncc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 1-propyl-3-(4-pyridylmethyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:3]1.[CH2:25]([O:35][C:36]1[CH:48]=[CH:47][C:39]([C:40](C2NC=CN=2)=[O:41])=[CH:38][CH:37]=1)/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]>O>[CH2:25]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([NH:1][CH:2]2[CH2:6][N:5]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=3)[N:4]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:3]2)=[O:41])=[CH:47][CH:48]=1)/[CH:26]=[C:27](/[CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])\[CH3:28]
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)c2ncc[nH]2)cc1
Reactant: COc1ccc(CN2CC(N)CN2Cc2ccc(OC)cc2)cc1
Solvent: O
Product: COc1ccc(CN2CC(NC(=O)c3ccc(OC/C=C(\C)CCC=C(C)C)cc3)CN2Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of 4-amino-1,2-bis(4-methoxyphenylmethyl)pyrazolidine (0.80 g) in tetrahydrofuran anhydride (20 ml) was added 4-geranyloxybenzoylimidazole (0.79 g). The mixture was stirred at room temperature for one night. The reaction solution, with water added thereto, was extracted with ethyl acetate. The extract was concentrated under a vacuum and the residue was purified by silica gel column chromatography (chloroform) and then recrystallized from ethyl acetate, thereby yielding 0.65 g (45%) of the aimed compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](O)=[O:13])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Cl:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)COc1ccc(Cl)cc1

Procedure:
Thionyl chloride (0.431 mole, 51.26 grams) was slowly added to p-chlorophenoxyacetic acid (0.287 mole, 53.5 grams) in 160 ml of benzene at room temperature. The reaction mixture was refluxed for 18 hours. The excess thionyl chloride and benzene were stripped from reaction mixture under vacuum (aspirator) and the residue p-chlorophenoxyacetyl chloride was distilled at 70°C./0.05 mm Hg.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=2)[C:26](O)=[O:27])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.O>[OH:27][CH2:26][C:25]1[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[N:31]=[C:23]([NH:22][CH:19]2[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:17][CH2:18]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)O)cc(C(F)(F)F)n2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(CO)cc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (1.1 mL, 8.6 mmol) was added to a solution of 2-{[1-(tert-butoxycarbonyl)piperidin-4-yl]amino}-6-(trifluoromethyl)isonicotinic acid (2.8 g, 7.2 mmol, from Step 2) and triethylamine (2.0 mL, 14 mmol) in tetrahydrofuran (30. mL) at 0° C. After stirring for 30 minutes, the reaction mixture was filtered through a short pad of celite into a flask containing a mixture of sodium tetrahydroborate (0.95 g, 25 mmol) in water (15 mL) at 0° C. The celite pad was rinsed with three portions of THF (3×30 mL) into the reaction flask. The reaction was allowed to warm to room temperature and stir for 1 hour. The reaction mixture was recooled in an ice bath and was quenched by the addition of saturated ammonium chloride solution. The product was extracted with a 150 mL portion of ethyl acetate. The organic layer was washed with water and brine, was dried over sodium sulfate, filtered and concentrated. Flash chromatography, using a 120 g silica gel cartridge and eluting with a gradient from 0-80% EtOAc in hexanes afforded product as a white solid (2.7 g, 100%). 1H NMR (400 MHz, CDCl3) δ 6.87 (s, 1H), 6.56 (s, 1H), 5.02-4.36 (m, 2H), 4.09-3.94 (m, 2H), 3.81 (dtt, J=14.2, 8.0, 3.9 Hz, 1H), 3.03-2.85 (m, 2H), 2.07-1.97 (m, 2H), 1.46 (s, 9H), 1.37 (qd, J=12.2, 3.8 Hz, 2H). 19F NMR (376 MHz, CDCl3) δ −69.21 (s). LCMS (M+Na)+: 398.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[Cl-].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:14]=1[CH2:15][Zn+]>O1CCCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:15][C:14]2[C:13]([Cl:12])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:7]=1
Reactant: N#Cc1ncc(Br)cc1Br
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: [Pd]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ncc(Cc2c(Cl)cccc2Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of the product of EXAMPLE 1A (4.52 g, 15.34 mmol) in tetrahydrofuran (75 mL) was treated with palladium tetrakis(triphenylphosphine) (0.887 g, 0767 mmol) and 2,6-dichlorobenzyl zinc chloride (46 mL, 0.5M in tetrahydrofuran). The mixture was heated at 85° C. for 1 hour. After cooling to ambient temperature, the mixture was diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% ethyl acetate in hexanes) provided the title compound. MS (LC-MS) m/z 342 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15](O)=[O:16].ClC(OCC)=O.Cl.[CH3:32][NH:33][OH:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:13]=[CH:14][C:15]([N:33]([CH3:32])[OH:34])=[O:16]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: CNO
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C=CC(=O)N(C)O)cc(OC)c1OC
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
Triethylamine (3.07 ml, 22 mmol) was added to a stirred solution of 3,4,5-trimethoxycinnamic acid (4.76 g, 20 mmol) in N,N-dimethylformamide (30 ml). The resulting solution was cooled to -12° C., and ethyl chloroformate (2.00 ml, 21 mmol) was added dropwise with stirring. After 15 minutes, solid N-methylhydroxylamine hydrochloride (1.84 g, 22 mmol) was added, followed by triethylamine (3.2 ml, 23 mmol). The mixture was allowed to warm to room temperature, stirred overnight, and poured into 150 ml of 1% aqueous citric acid. The mixture was extracted twice with ethyl ether, and the combined extracts washed successively with water and brine, then dried over MgSO4, filtered, and evaporated. The residue was recrystallized from ethyl acetate to provide 1.82 g (34% yield) of the titled compound as colorless crystals, mp 169°-170° C.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25](=[O:32])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:42][Mg]Br.C(OCC)(=O)C>C1COCC1>[F:39][C:36]([F:37])([F:38])[C:34]1[CH:33]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([OH:32])([CH3:42])[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)CC2CCCC2)n1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(C)(O)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2-H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl-2-cyclopentylethanone (160 mg, 0.269 mmol) in anhydrous THF (10 mL) at 0° C. was added methylmagnesium bromide (3.0 M solution in THF, 0.359 mL, 1.07 mmol). After stirring for 30 minutes the solution was warmed to room temp and stirred for 1.5 hours. After 1.5 hours solution was portioned between 2 N HCL (10 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 10 minutes before the layers were separated. The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organics layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil. (160 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H) 7.67(s, 2H) 7.38 (m, 3H) 5.32 (d, J=16.6 Hz, 1H) 5.01 (d, J=16.6 Hz, 1H) 4.78 (s, 2H) 4.13 (s, 3H) 1.92 (dd, J=5.4 Hz, J=5.4 Hz) 1.80 (dd, J=5.81 Hz, J=6.24 Hz) 1.64 (m, 2H) 1.59 (s, 3H) 1.54 (m, 3H) 1.35 (m, 2H) 0.88 (m, 2H). LC-MS Calc. 609.5, found 610.5 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][N:15]=[N+]=[N-])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2].[ClH:22]>CO.[Pd].C(O)C>[ClH:22].[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[N:8]([CH:19]=1)[C@@H:9]1[O:18][C@H:13]([CH2:14][NH2:15])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reaction time: 3 h

Procedure:
0.80 g of 5-acetyl-5'-azido-2',5'-dideoxyuridine was dissolved in 100 ml of methanol and 10 ml of 0.27M hydrogen chloride in methanol were added. 0.1 g of 5% palladium-on-charcoal catalyst was added as a slurry in ethanol and the mixture was hydrogenated for 3 hours at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 0.91 g of hygro-scopic 5-acetyl-5'-amino-2',5'-dideoxyuridine hydrochloride of melting point 73°-85° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[N:9]([C:19]3[N:20]=[CH:21][N:22]=[C:23]([NH2:26])[C:24]=3[N:25]=2)[C@@H:10]2[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]2[OH:12])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(OCC)C.C(OC(=O)C)C.C(O)C>[CH3:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]3[N:9]([C:19]4[N:20]=[CH:21][N:22]=[C:23]([NH2:26])[C:24]=4[N:25]=3)[C@@H:10]3[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[C@H:11]3[OH:12])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1
Reactant: Nc1ncnc2c1nc(NCc1ccc(Br)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ccc(CNc3nc4c(N)ncnc4n3[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)cc2)cc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a mixture of 8-(4-bromobenzylamino)adenosine (0.050 g), 4-methylphenylboronic acid (0.017 g), sodium carbonate (0.024 g), water (0.4 mL) and ethanol (2.2 mL) was added tetrakis-(triphenylphosphine)palladium(0) (0.006 g), and the resulting mixture was stirred under reflux for 22 hours. The reaction mixture was cooled to room temperature. After addition of dichloromethane/methanol (5/1, 35 mL), the insoluble material was filtered out. The filtrate was concentrated under reduced pressure. The residue was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK C18MG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, eluent: water/methanol=70/30-10/90) to give the title compound (0.022 g).
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.[CH3:28][C:29]1([O:32][CH2:31]1)[CH3:30].[Br-].[Li+].CN1C(=O)CCC1>O.C(OCC)(=O)C>[OH:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:27])[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]3[CH2:3][CH2:4][C@:5]4([CH2:9][CH2:8][N:7]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])[CH2:6]4)[CH2:1]3)=[CH:11][CH:12]=1)[CH2:25][CH2:24]2
Reactant: O=C1c2ccc(O)cc2CCN1c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Reactant: CC1(C)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(O)CN1CC[C@]2(CCN(c3ccc(N4CCc5cc(O)ccc5C4=O)cc3)C2)C1
Temperature: 65 °C

Procedure:
A mixture of 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.50 g), isobutylene oxide (0.10 g), lithium bromide (0.12 g) and NMP (1 mL) was heated at 65° C. for 5 hours. The cooled reaction mixture was distributed between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated. In this way the product was obtained with molecular weight 435.57 (C26H33N3O3); MS (ESI): 436 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:22]([C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:17][CH:18]=1)([OH:24])=[O:23]
Reactant: CCOC(=O)c1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Product: O=C(O)c1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 141 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(1H-imidazol-1-yl)propanamide (61.9 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (44.4 mg).
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][OH:24])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1.CC(C)=O>C(O)(C)C>[Cl:14][C:15]1[C:20]([NH:21][C:22]([CH3:26])([C:23]([OH:3])=[O:24])[CH3:25])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(CO)Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: CC(C)(Nc1c(Cl)cccc1[N+](=O)[O-])C(=O)O

Procedure:
Jones reagent (2.67 M) is added in aliquots (30 ml, 15 ml, 10 ml, 5 ml) every 15 min to a solution of 2-[N-(6-Chloro-2-nitrophenyl)]amino-2-methyl-1-propanol (IX, EXAMPLE 13, 21.6 g) and acetone (1.65 l) at 0° until the reaction is done as measured by TLC analysis. After 1 hr total time, isopropanol (90 ml) is added and the mixture is allowed to warm to 20°-25°. The mixture is filtered and the solids washed with acetone several times. The combined filtrates are concentrated and partitioned between ether (1.01) and potassium hydroxide (10%, 3×100 ml). The basic layer is acidified (3 N hydrochloric acid) and extracted with methylene chloride (3×200 ml). The methylene chloride phase is dried over magnesium sulfate, filtered, and concentrated to give the title compound sufficient pure to be used in the next step without additional purification, mp 107°-109°; IR (mineral oil) 3358, 2953, 2924, 1715, 1597, 1496, 1330, 1280, 1231, 1174, 1105 and 747 cm-1 ; NMR (CDCl3) 8.00, 7.61, 7.06, 6.5-7.1 and 1.54 δ; MS (m/z) 258 and 213.
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:19]=[CH:18][C:14]([NH:15][CH2:16][CH3:17])=[CH:13][C:12]=2[CH3:20])(=O)=O)=CC=1.[CH3:22][S:23]([NH:26][CH2:27][CH2:28]Cl)(=[O:25])=[O:24].C(=O)([O-])O.[Na+].S(=O)(=O)(O)O>C(O)(C)C.CO.O>[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([N:15]([CH2:28][CH2:27][NH:26][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:16][CH3:17])=[CH:13][C:12]=1[CH3:20]
Reactant: CS(=O)(=O)NCCCl
Reactant: CCNc1ccc(NS(=O)(=O)c2ccc(C)cc2)c(C)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: CCN(CCNS(C)(=O)=O)c1ccc(N)c(C)c1

Procedure:
A mixture of 7g of 4-(N-p-toluenesulfonyl)amino-3-methyl-N-ethylaniline, 4g of β-methanesulfonamidoethyl chloride, 2.1g of sodium hydrogen carbonate, 16g of water and 30ml of methanol were refluxed for 5 hours, and then 16g of sulfuric acid were added thereto and the entire reaction system was again refluxed. Next, the reaction solution was condensed to half the original volume and 300ml of isopropyl alcohol were added thereto to separate crystals. The crystals were filtered out and dried to obtain 1.5g of 4-amino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline. sesquisulfate. H2O.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:18][C:19]1[CH:20]=[C:21]([O:28][CH3:29])[CH:22]=[C:23]2[C:27]=1[NH:26][CH2:25][CH2:24]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:26]2[C:27]3[C:23](=[CH:22][C:21]([O:28][CH3:29])=[CH:20][C:19]=3[Cl:18])[CH2:24][CH2:25]2)[C:3](=[O:16])[N:4]([CH:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(C1CCC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CCC(C1CCC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-cyclobutylpropyl)-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials to give a yellow oil. 1H NMR (300 MHz, CDCl3): δ 6.74 (s, 2H), 6.67 (s, 1H), 4.90-4.80 (m, 1H), 4.34 (t, J=7.9 Hz, 2H), 3.78 (s, 3H), 3.10 (t, J=7.7 Hz, 2H), 2.60-2.50 (m, 1H), 2.18-2.12 (m, 1H), 1.90-1.70 (m, 6H), 1.55-1.43 (m, 1H), 0.84 (t, J=7.5 Hz, 3H); HRMS (ESI) m/z 408.1270 [(M+H)+, calcd for C20H24N3O2Cl2 408.1246].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:24])[CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:25](Br)[CH3:26].[H-].[Na+].[NH4+].[Cl-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:24])[CH2:12][CH2:13][O:14][CH2:25][CH3:26])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCBr
Reactant: COc1ccc(C(CCO)N2Cc3ccccc3C2=O)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOCCC(c1ccc(OC)c(OC)c1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a stirred solution of 3-(3',4'-dimethoxyphenyl)-3-(1'-oxoisoindolinyl)-1-propanol (500 mg, 1.53 mmol), ethyl bromide (0.27 mL, 3.62 mmol) and tetrabutyl ammonium iodide (60 mg, 0.16 mmol) in THF (10 mL) at room temperature, was added NaH (160 mg, 60%, 4.0 mmol). The mixture was stirred at room temperature for 4 h. To the mixture was added NH4Cl (20 mL, sat). The organic layer was separated. The aqueous layer was extracted with methylene chloride (2×25 mL). The combined organic layer was dried over magnesium sulfate. Removal of solvent and chromatography (silica gel 120 grams, 1:6 EtOAc:CH2Cl2) gave 3-(3',4'-dimethoxyphenyl)-1-ethoxy-3-(1'-oxoisoindolinyl)propane as an oil, (420 mg, 77% yield): 1H NMR (CDCl3)δ1.09 (t, J=7 Hz, 3H, CH3), 2.35-2.45 (m, 2H, CH2), 3.35-3.58 (m, 4H, CH2 OCH2), 3.84 (s, 3H, CH3), 3.86 (s, 3H, CH3), 4.00 (d, J=16.8 Hz, 1H, NCHH), 4.35 (d, d=16.8 Hz, 1H, NCHH), 5.66 (dd, J=6, 9.3 Hz, 1H, NCH), 6.82-6.98 (m, 3H, Ar), 7.35-7.53 (m, 3H, Ar), 7.84-7.88 (m, 1H, Ar); 13C NMR (CDCl3)δ15.02, 31.62, 45.82, 51.51, 55.82, 55.90, 66.39, 67.86, 110.90, 111.27, 119.15, 122.68, 123.71, 127.86, 131.16, 132.28, 132.73, 141.28, 148.49, 149.08, 168.38; Anal Calcd for C21H25NO4 0.3H2O: C, 69.90; H, 7.15; N, 3.88. Found: C, 69.69; H, 6.80; N, 3.73.