Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH2:19][CH:20]=[CH2:21])[CH3:3].[OH-:22].[Na+].OO.Cl>O1CCCC1.CCOCC.C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][C:9]=1[CH2:19][CH2:20][CH2:21][OH:22])[CH3:3]
Reactant: C=CCc1cc(OCCCC)ccc1OCCCN(C)C
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(OCCCN(C)C)c(CCCO)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of N,N-dimethyl-3-(2-allyl-4-butoxyphenoxy)propylamine (1.8 g) in tetrahydrofuran (3 ml) was added dropwise over a period of 3 minutes to a solution of borane tetrahydrofuran complex (1M, 12.4 ml) at a temperature of 0° C. and under an atmosphere of argon. The reaction mixture was stirred at 0° C. for 3 hours. Ethanol (10 ml) was added to the reaction mixture, followed by aqueous 6N aqueous sodium hydroxide and hydrogen peroxide solution (30%, 12 ml). The mixture was then heated at 50° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature, extracted with ethyl acetate, the ethyl acetate extracts dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel (Merck Art No 9385) using a 40:60:0.2 mixture of ethyl acetate, hexane and triethylamine as eluent to give an oil. The oil was dissolved in ether and excess ethereal hydrogen chloride added until crystallisation began. The solid was collected by filtration and dried to give N,N-dimethyl-3-[4-butoxy-2-(3-hydroxypropyl)phenoxy]propylamine as a white solid (60 mg), m.p. 118° C.; microanalysis, found: C, 62.4; H, 9.6; N, 4.0% C18H32NO3Cl requires: C, 62.5; H, 9.32; N, 4.05%; NMR ([CD3 ]2SO+CD3COOD): 0.95(3H,t), 1.45(2H,m), 1.7(4H,m), 2.2(2H,m), 2.58(2H,t), 2.89(6H,s), 3.35(2H,t), 3.55(2H,t), 3.9(2H,t), 4.02(2H,t), 6.72(2H,m) and 6.82(1H,s); m/z 310(M+H).
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:12][CH:13]=[N:14][N:15]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[O:12]1[CH:13]=[N:14][N:15]=[C:11]1[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH:2]([OH:1])[CH2:16][N:28]1[CH2:27][CH2:26][N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH3:17])[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1ccc(-c2nnco2)c(OCC2CO2)c1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2ccccc2-c2nnco2)CC1

Procedure:
7.3 g (0.033 mole) of 2,3-epoxypropoxy-2-(1,3,4-oxadiazol-2-yl)-benzene from Example VII and 6.4 g (0.033 mole) of 2-methoxy-phenylpiperazine in 50 ml of ethanol are refluxed for 17 hours. The solvent is stripped off on a rotary evaporator and the oily residue is taken up in methylene chloride. The solution is washed with 3×50 ml of water, dried over anhydrous sodium sulfate, filtered and concentrated. 12.6 g (93% of theory) of a pale yellow oil are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH2:14]1[CH2:19][O:18][CH:17]=[CH:16][CH2:15]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>ClCCl>[O:18]1[CH2:19][CH2:14][CH2:15][CH2:16][CH:17]1[O:1][CH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(CCO)OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(CCOC1CCCCO1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a mixture of benzyl 3-hydroxypropanoate (3.35 g, 18.6 mmol) and DHP (3.12 g, 37.2 mmol, Alfa) in dichloromethane (100 mL) was added PPTS (5.6 g, 22.3 mmol, Aldrich) in portions. The reaction mixture was stirred at rt overnight, and was quenched with 50 mL of H2O. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10:1 (v/v) petroleum ether/EtOAc) to give the title compound as colorless oil (4.25 g, 86%).
Reaction SMILES: C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1)C.[CH3:41][S:42][C:43]1[CH:48]=[CH:47][C:46]([N:49]=[C:50]=[O:51])=[CH:45][CH:44]=1.[C:52]([O:56][CH2:57][CH2:58][OH:59])(=[O:55])[CH:53]=[CH2:54].[N-]=C=O>C(OCC)(=O)C>[C:52]([O:56][CH2:57][CH2:58][O:59][C:50](=[O:51])[NH:49][C:46]1[CH:47]=[CH:48][C:43]([S:42][CH3:41])=[CH:44][CH:45]=1)(=[O:55])[CH:53]=[CH2:54]
Reactant: CSc1ccc(N=C=O)cc1
Reactant: C=CC(=O)OCCO
Agent: CN(C)CCCN1CN(CCCN(C)C)CN(CCCN(C)C)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCOC(=O)Nc1ccc(SC)cc1
Temperature: 60 °C

Procedure:
0.02 g of 2,6-di-tert-butyl-4-methylphenol, 0.01 g of Desmorapid Z, 4.7 g of 4-(methylthio)phenyl isocyanate in 25 g of ethyl acetate were initially introduced into a 100 ml round-bottomed flask and heated to 60° C. Thereafter, 4.1 g of 2-hydroxyethyl acrylate were added dropwise and the mixture was kept further at 60° C. until the isocyanate content had fallen below 0.1%. Thereafter, the ethyl acetate was distilled off at 5 mbar and cooling was effected. The product was obtained as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.[Cl-].C[Al+]C.[CH3:23][CH:24]1[CH2:29][C:28](=[O:30])[O:27][C:26](=[O:31])[CH2:25]1>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:5]2[C:28](=[O:30])[CH2:29][CH:24]([CH3:23])[CH2:25][C:26]([OH:31])=[O:27]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: CCCCCCCc1cc2cc(Cl)ccc2n1C
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCc1c(C(=O)CC(C)CC(=O)O)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-heptyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution 4-methyl-dihydro-pyran-2,6-dione was added at 0° C. and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=2)(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-acetamidobenzene-1-sulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=[O:19])[CH3:18])=[CH:4][S:5][C:6]=1[C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11]C[C:9]=2[CH:8]=1.C1C2C(=CC(C3SC=C(C(=O)C)C=3OC)=CC=2)CC1>>[CH2:13]1[C:14]2[C:9](=[CH:8][C:7]([C:6]3[S:5][CH:4]=[C:3]([C:17](=[O:19])[CH3:18])[C:2]=3[OH:1])=[CH:16][CH:15]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Agent: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCC2
Product: CC(=O)c1csc(-c2ccc3c(c2)CCC3)c1O
Yield: 37.3 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (6) in Reference Synthetic Example 3 by using 3.5 g (0.0129 mol) of 1-[5-(2,3-dihydro-1H-inden-5-yl)-4-methoxythiophen-3-yl]ethanone to obtain 1.24 g of the desired product (yield: 37.3%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[OH-].[Na+]>O1CCCC1.O>[CH2:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: CCOC(=O)[C@@H]1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CCOC[C@H]1C(=O)OCC

Procedure:
To a solution of ethyl (3S)-morpholine-3-carboxylate (3.80 g) in a mixture of tetrahydrofuran (40 ml) and water (40 ml) was added a solution of allyl chloroformate (3.36 ml), in tetrahydrofuran (3 ml) under ice-cooling with stirring, keeping the pH between 8.5 and 9.5 with 4N aqueous sodium hydroxide. After stirring for 30 minutes, the mixture was extracted with ethyl acetate (100 ml), dried over magnesium sulfate, and evaporated to give ethyl (3S)-4-allyloxycarbonylmorpholine-3-carboxylate (5.83 g) as a syrup.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CN(C=O)C>[CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[N:5]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:4]=2[CH2:3]1
Reactant: CC1(c2ccccn2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccccn2)CN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
2,6-Dimethyl-2,3,4,9-tetrahydro-1H-β-carboline (500 mg, 2.5 mmol) was dissolved in 20 mL DMF and stirred for 10 min at RT. Sodium hydride (180 mg, 7.5 mmol) was added portionwise at RT and the mixture stirred for 10 min. 2-(2-Methyl-oxiranyl)-pyridine (472 mg, 3.5 mmol) was added dropwise at the same temperature and stirred for 12 h at RT. The reaction was monitored by TLC & LCMS. After consumption of starting material, the reaction mixture was quenched with ice water and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated and the residue was crystallized in hexane to obtain 115 mg of 1-(2,6-dimethyl-1,2,3,4-tetrahydro-β-carbolin-9-yl)-2-pyridin-2-yl-propan-2-ol. 1HNMR (CDCl3, freebase) δ (ppm): 8.51 (d,1H), 7.65 (t,1H), 7.29 (d, 1H), 7.22 (d,1H), 7.20 (s,1H), 6.95 (d,1H), 6.85 (d, 1H), 4.9 (bs,1H), 4.18 (s, 2H), 3.21 (dd, 2H), 2.77 (m, 2H), 2.69 (m, 2H), 2.42 (d, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers 16a and 16b. Optical rotations: Compound 16a, (−)5.77(c 0.52, Chloroform, 98.11% HPLC purity); Compound 16b, (+)5.85 (c 0.51, Chloroform, 98.06% HPLC purity).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[C:16]([O:19][CH2:20][C:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22])(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC(C1C=CC(S(N)(=O)=O)=CC=1)(C)C)(=O)C.CS(C)=O>[C:16]([O:19][CH2:20][C:21]([C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:33][C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=2)(=[O:31])=[O:32])=[CH:28][CH:29]=1)([CH3:23])[CH3:22])(=[O:18])[CH3:17]
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: CC(=O)OCC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)OCC(C)(C)c1ccc(S(=O)(=O)Nc2ncnc(Cl)c2-c2ccc(C)cc2)cc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A mixture of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (10.0 g), 4-(2-acetoxy-1,1-dimethylethyl)benzenesulfonamide (11.58 g), potassium carbonate (14.45 g) and dimethyl-sulfoxide (50 ml) is stirred at 75° C. (bulk temperature) for 3 hours, and thereto is further added 4-(2-acetoxy-1,1-dimethylethyl)benzenesulfonamide (0.34 g). The mixture is stirred at 70-75° C. for 1.5 hour, and the reaction mixture is cooled, and poured into a mixture of ice (100 g) and conc. hydrochloric acid (60 ml). The mixture is extracted with ethyl acetate, and the organic layer is washed, dried, and concentrated under reduced pressure. The residue is crystallized from a mixture of ethyl acetate and diisopropyl ether to give 4-(2-acetoxy-1,1-dimethylethyl)-N-{6-chloro-5-(4-methylphenyl)pyrimidin-4-yl}benzenesulfonamide (14.97 g) as colorless needles.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH2:11])=[CH:8][CH:9]=[CH:10][C:2]1=2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=[CH:10][C:2]1=2
Reactant: Nc1cccc2c1OCCO2
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: CC(=O)Nc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxin-5-amine (Intermediate B3, 4.5 g, 30 mmol) in ethanol (50 mL) at room temperature was slowly added acetic anhydride (3.0 g, 30 mmol). After the addition was over, the mixture was stirred at room temperature for 5 minutes. The resulting suspension was concentrated to give the crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate 4/1) to afford the product N-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)acetamide (5.5 g, yield 95%). 1H NMR (400 MHz, CDCl3) δ ppm 9.12 (s, 1H), 7.44-7.46 (d, 1H, J=8.0 Hz), 6.71-6.75 (t, 1H, J=8.0 Hz), 6.59-6.61 (d, 1H, J=7.6 Hz), 4.23-4.30 (m, 4H), 2.06 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16](Cl)(=[O:18])=[O:17])[CH:8]=2)[NH:3]1.[C:20]1([NH2:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>>[C:20]1([NH:26][S:16]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH:11]=[C:10]3[C:12]([F:15])([F:14])[F:13])(=[O:18])=[O:17])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: Nc1ccccc1
Solvent: c1ccncc1
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Nc3ccccc3)ccc2[nH]1
Yield: 18.7 %

Procedure:
Following the same procedure as Example 1, condensation of 2-oxo-4-trifluoromethyl-1,2-dihydroquinoline-6-sulfonyl chloride (Preparation 3, 50 mg, 160 μmol) with PhNH2 (15 μL, 168 μmol), employing pyridine (14 μL, 168 μmol) as base, gave the title compound (11 mg, 17%): δH ((CD3)2SO)=7.00 (s, 1H), 7.05–7.10 (m, 3H), 7.20 (m, 2H), 7.50 (d, 1H), 7.90 (dd, 1H), 8.00 (d, 1H); m/z (ES+)=369.1 [M+H]+.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13])([O-:5])=[O:4].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>CN(C=O)C.CCOC(C)=O>[CH2:26]([N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N+:3]([O-:5])=[O:4])(=[O:14])=[O:13])[CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCBr
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
Crushed KOH (0.0484 g, 0.862 mmol, 1.2 equiv) was added to 2-nitro-N-phenylbenzenesulfonamide (0.200 g, 0.719 mmol) in 1 mL DMF, and the mixture was stirred for 30 min. 4-Bromo-1-butene (0.2426 g, 1.80 mmol) in 2 mL DMF solution was added dropwise into the mixture and it was stirred at room temperature overnight. The reaction mixture was diluted with 30 mL EtOAc and washed with 1M HCl 2×10 mL and water 3×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.1546 g white solid, yield 63.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH2:36][C:37]6[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=6[C:45]6[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=6)[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:21]=4[C:22]([O:24]C)=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:30]5[CH2:31][CH2:32][N:33]([CH2:36][C:37]6[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=6[C:45]6[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=6)[CH2:34][CH2:35]5)[CH:27]=[CH:26][C:21]=4[C:22]([OH:24])=[O:23])[C:13]=3[N:12]=[CH:11]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C(c2ccc(OC)cc2)n2cnc3c(Oc4cc(N5CCN(CC6=C(c7ccc(Cl)cc7)CC(C)(C)CC6)CC5)ccc4C(=O)O)cccc32)cc1
Temperature: 50 °C

Procedure:
To a solution of EXAMPLE 403F (545 mg) in a mixture of methanol (7.50 mL) and tetrahydrofuran (7.50 mL) was added a solution of sodium hydroxide (269 mg) in water (3.0 mL). The reaction mixture was heated at 50° C. for 18 hours and then concentrated. The residue was mixed with water (100 mL) and the pH was adjusted to ca. 7 with 1M aqueous hydrochloric acid. The mixture was extracted with 10% methanol in methylene chloride (10×50 mL), and the combined organic layers were concentrated to provide the title compound.
Reaction SMILES: C([O:8][C:9](=[O:65])[CH2:10][C:11]1([CH2:54][C:55](=[O:64])[O:56]CC2C=CC=CC=2)[O:15][N:14]=[C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23](=[O:33])[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)[CH:19]=[CH:18][C:17]=2[CH2:34][CH2:35][C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([O:46]CC3C=CC=CC=3)=[O:45])[CH2:40][CH2:39]2)=[O:37])[CH2:12]1)C1C=CC=CC=1>[Pd].C1COCC1>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:23]([O:22][C:20]2[CH:19]=[CH:18][C:17]([CH2:34][CH2:35][C:36]([N:38]3[CH2:43][CH2:42][CH:41]([C:44]([OH:46])=[O:45])[CH2:40][CH2:39]3)=[O:37])=[C:16]([C:13]3[CH2:12][C:11]([CH2:10][C:9]([OH:65])=[O:8])([CH2:54][C:55]([OH:64])=[O:56])[O:15][N:14]=3)[CH:21]=2)=[O:33])=[CH:29][CH:28]=1
Reactant: O=C(CC1(CC(=O)OCc2ccccc2)CC(c2cc(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2CCC(=O)N2CCC(C(=O)OCc3ccccc3)CC2)=NO1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(=O)Oc2ccc(CCC(=O)N3CCC(C(=O)O)CC3)c(C3=NOC(CC(=O)O)(CC(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.6 %

Procedure:
A mixture of benzyl 1-(3-(2-(5,5-bis(2-(benzyloxy)-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-((4-nitrobenzoyl)oxy)phenyl)propanoyl)piperidine-4-carboxylate (939 mg), 10% Pd/C (containing about 55% water, 100 mg), and THF (10 mL) was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure to obtain the title compound (716 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]=1[CH2:23][CH3:24].[NH2:26][NH2:27]>>[CH2:23]([C:6]1[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([C:5]=1[CH2:4][C:3]([NH:26][NH2:27])=[O:2])=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH3:24]
Reactant: CCc1c(CC(=O)OC)c2cc(OC)ccc2n1Cc1ccccc1
Reactant: NN
Product: CCc1c(CC(=O)NN)c2cc(OC)ccc2n1Cc1ccccc1
Yield: 74 %

Procedure:
Using the method described in Example 3, Part C, 748 mg 2.2 mmol) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid methyl ester was reacted with 2.2 mL of hydrazine to give 552 mg (74% yield) of 2-ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetic acid hydrazide, that crystallized out of the reaction mixture on cooling (melting point, 138-140° C.).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1>>[CH:31]1([NH:34][C:14]([C:7]2([CH3:17])[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=3[CH3:18])[O:8]2)=[O:16])[CH2:33][CH2:32]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: NC1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC1CC1)O2
Yield: 39.2 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 357 mg CDI (2.00 mmol) and 126 mg cyclopropylamine (2.2 mmol) produced 227 mg of N-cyclopropyl-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70]([F:73])([F:72])[F:71])=[CH:66][N+:65]=1[O-]>[Fe].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([F:72])([F:71])[F:73])=[CH:66][N:65]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1ccc(C(F)(F)F)c[n+]1[O-]
Agent: [Fe]
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(C(F)(F)F)cn3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 28.9 %

Procedure:
The title compound was prepared by following the procedure described for Example-121 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.200 g, 0.537 mmol), COMU (0.873 g, 1.34 mmol), DIPEA (0.173 g, 1.34 mmol) and 2-amino-5-(trifluoromethyl)pyridine 1-oxide (Intermediate-41, 0.105 g, 0.591 mmol), iron powder (0.050 g) and acetic acid (5.0 mL) to afford 0.080 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 2.24 (s, 3H), 3.13 (s, 2H), 7.25-7.33 (m, 2H), 7.42 (d, J=7.5 Hz, 1H), 7.56 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.75 (s, 1H), 9.16 (m, 1H), 10.49 (s, 1H), 10.99 (s, 1H); MS [M]+: 516.06.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[NH:33][C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]1)[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([NH:4][C:5]([CH:26]1[CH2:32][C@H:31]2[N:33]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([Cl:34])=[CH:36][CH:37]=3)[C@H:28]([CH2:29][CH2:30]2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21][C:20]([CH3:22])([CH3:23])[C:19]([CH3:24])([CH3:25])[O:18]1)[C:6]([NH:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)C1C[C@H]2CC[C@@H](C1)N2Cc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
A solution of 2-acetamido-2-{(1R,5S)-8-azabicyclo[3.2.1]octan-3-yl}-N-tert-butyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide (170 mg, 0.37 mmol) and 4-chlorobenzaldehyde (104 mg, 0.74 mmol) and acetic acid (44 mg, 41 μL, 0.74 mmol) in 1,2-dichloroethane (1 mL) was stirred at room temperature for 30 minutes and then treated with sodium triacetoxyborohydride (196 mg, 0.93 mmol). After 24 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), diluted with saturated aqueous sodium chloride (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic phase was collected, dried over MgSO4, filtered and concentrated to give 2-acetamido-N-tert-butyl-2-{(1R,5S)-8-(4-chlorobenzyl)-8-azabicyclo[3.2.1]octan-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-hexanamide as a pale yellow oil which was used immediately in the next step; m/z for C32H51BClN3O4 expected 587.4. found 589.7 (M+H(37Cl))+, 588.0 (M+H(35Cl))+,