Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([NH:11][CH3:12])=[O:10].[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:13])[C:9]([NH:11][CH3:12])=[O:10]
Reactant: CNC(=O)C(=O)c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNC(=O)C(O)c1ccccc1C

Procedure:
Racemic 2-(2-methyl-phenyl)-N-methyl-2-hydroxy-acetamide was synthesized by reducing 2-(2-methyl-phenyl)-N-methyl-2-oxo-acetamide with NaBH4 in methanol.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1.[CH3:41][S:42]([OH:45])(=[O:44])=[O:43]>>[S:42]([OH:45])(=[O:44])(=[O:43])[CH3:41].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 2 (10.5 g, 21.1 mmol) in 34 mL (6.0 eq) of 4.0 N HCl/1,4-dioxane was stirred at room temperature for 1 h. Methanesulfonic acid (1.48 mL, 22.8 mmol) was slowly added to the reaction mixture while stirred at room temperature. The solution was concentrated under vacuum to afford the mesylate salt 1 as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]([C:12]([F:15])([F:14])[F:13])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[N:8]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:9]([C:12]([F:13])([F:14])[F:15])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Agent: [Pd]
Product: Nc1ccc2c(c1)OCC(C(F)(F)F)N2CC(F)(F)F
Yield: 54.1 %

Procedure:
This compound was prepared by General Method 4 (EXAMPLE 1) from (+)-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine (45 mg, 0.16 mmol) and 10% Pd-C (30 mg) and purified by flash chromatography (EtOAc:hexanes, 1:1) to afford 26 mg (65%) of (±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine. Data for (±)-7-amino-3,4-dihydro-4-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-2H-1,4-benzoxazine: 1H NMR (400 MHz, CDCl3) 6.68 (d, 1H, J=8.4), 6.32-6.28 (m, 2H), 4.56 (dd, 1H, J=12.0, 0.96), 4.16-4.00 (m, 2H), 3.84-3.69 (m, 2H), 3.60-3.32 (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[N:7][CH:6]=1)C.[BH4-].[Na+]>CO>[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cncc(Br)c1

Procedure:
To a cold (0° C.) solution of ethyl-5-bromonicotinate (1.0 g, 4.3 mmoL) in MeOH (15 mL) was added sodium borohydride (650 mg, 17 mmol) portion wise. After 30 min. the reaction was quenched by the addition of water (10 mL). The reaction was then extracted with methylene chloride (3×). The extracts were combined, dried (MgSO4) the filtrate was concentrated and purified by column chromatography on silica gel (0 to 80% ethyl acetate/hexanes) to produce 475 mg (60%) as a clear oil. 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.49 (s, 1H), 7.91 (s, 1H), 4.73 (s, 2H), 2.51 (s, br, 1H). Mass spec.: 188.12 (MH)+.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[N:7][CH:6]=1)C.[BH4-].[Na+].[ClH:15].[OH-].[Na+].Cl.CCO>C(O)C.O>[ClH:15].[Br:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[N:7][CH:8]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cncc(Br)c1
Reaction time: 8 h

Procedure:
5-Bromo nicotinic acid ethyl ester (25 g, 108 mmol) was dissolved in ethanol (500 ml) and treated with fresh sodium borohydride (25 g, 660 mmol) added portionwise over 30 min. at 20° C. Stirring was continued overnight under an argon atmosphere. Following this 1N HCl (50 ml) was added slowly (over 20 min) followed by 2N NaOH (25 ml) and H2O (75 ml) and this mixture was stirred for 2 h at ambient temperature. After evaporation of the alcohol the aqueous phase was extracted with dichloromethane (4×150 ml) and the combined extracts were washed with brine then dried with Na2SO4, filtered and evaporated. The resulting yellow oil was dissolved in a small volume of ethanol and treated with 0.93 M HCl/EtOH (62 ml, 1.2 eq.) at 4° C. over 1 h to afford, after removal of solvent and drying under high vacuum at 50° C. for 16 h, the title compound (10.9 g, 44%) as a light yellow solid. MS: m/e=186.9 (M+).
Reaction SMILES: O=[C:2]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17])[C:3]([OH:5])=[O:4].[C:18](=[O:22])([O:20][CH3:21])[NH2:19]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:18]([NH:19][C:2]1[C:3](=[O:5])[O:4][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH:6]=1)=[O:22]
Reactant: COc1cccc(C=CC(=O)C(=O)O)c1OC
Reactant: COC(N)=O
Solvent: Cc1ccccc1
Product: COC(=O)NC1=CC(c2cccc(OC)c2OC)OC1=O
Temperature: 105 °C
Yield: 94 %

Procedure:
300 g of 2-keto-4-(2,3-dimethoxyphenyl)-3-butenoic acid, 2680 ml of toluene, 13.4 g of p-totuenesulfonic acid and 133.8 g of methyl carbamate are placed into a 6 l 4-necked round-bottomed flask in an oil-bath, the mixture is heated to 105° C. for 4 hours with stirring, and the present water is removed azeotropically, the mixture is filtered and the solution is evaporated to dryness under vacuum, then the residue is triturated for about 2 hours with 1260 ml of Et2O, filtered washing with petroleum ether (40°-70° C.) and dried under vacuum at 60° C. 313.00 g are obtained. (Yield 94%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 77 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), 5 mL of acetone, and 5 mL of acetonitrile. The resulting mixture was refluxed under stirring at 79-75° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 99.3%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 82.5 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 3.17 g (19.8 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of acetonitrile. The resulting mixture was refluxed under stirring at 80-85° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 1.41 g (reaction yield: 98.9%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCCl)c(OC)c1
Temperature: 54.5 °C
Reaction time: 5 h
Yield: 59.8 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser were placed 1.02 g (5.49 mmol) of methyl 4-hydroxy-3-methoxybenzoate (purity: 98 wt. %), 2.12 g (13.2 mmol) of 3-bromo-1-chloropropane (purity: 98 wt. %), 1.16 g (8.24 mmol) of potassium carbonate (purity: 98 wt. %), and 10 mL of N,N-dimethylformamide. The resulting mixture was refluxed under stirring at 52-57° C. in an argon gas atmosphere for 5 hours. After the reaction was complete, the reaction mixture was filtered. Analysis of the filtrate by high performance liquid chromatography (absolute quantitative analysis) indicated that 0.85 g (reaction yield: 59.8%) of methyl 4-(3-chloropropoxy)-3-methoxybenzoate was produced.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[CH:14]([Li])(CC)[CH3:15].C(I)C>C1COCC1.C1CCCCC1>[CH2:1]([C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7])[CH2:14][CH3:15]
Reactant: [Li]C(C)CC
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCI
Product: CCCc1cccc2c1C(=O)NS2(=O)=O
Yield: 89 %

Procedure:
Following a procedure similar to that described in Preparation 16A, 10 g (0.051 mol) of 4-methylsaccharin in THF was reacted with 86 ml (0.10 mol) of a 1.18M solution of s-butyl lithium in cyclohexane and the resulting solution treated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of 4-propylsaccharin, which, on reaction with 5.32 ml (0.056 mol) of chloromethyl phenyl sulfide in toluene in the presence of tetrabutylammonium bromide, afforded a crude mixture from which was isolated by flash chromatography on silica gel 2-phenylthiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) of which, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDC, afforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([O:19][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Boc-4-iodophenylalanine was dissolved in acetonitrile and DUB (1 equivalent) was added followed by benzyl bromide (1 equivalent). The mixture was stirred for 2 h at room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in EtOAc and the solution washed with 10% aqueous HCl and water. Drying (MgSO4) and concentration under reduced pressure gave a crude product that was purified by crystallization from hexane.
Reaction SMILES: [OH-].[K+].C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1)=O)C>O.C(O)=C>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:9]1
Reactant: CCOC(=O)N1CCOC(C=C2c3ccccc3CCc3ccccc32)C1
Agent: C=CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1

Procedure:
Potassium hydroxide (3.0 g) in water was added to the above-obtained 5-(4-ethoxycarbonylmorpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (2.49 g) in ethenol, and the resulting mixture was heated under reflux for 8 hours. After cooling, ethanol was distilled off and water was added to the resulting residue. The resultant mixture was extracted with chloroform. The chloroform extract was dried, evaporated and chromatographed to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 221° - 224° C (oxalate).
Reaction SMILES: C(O[CH:5]([CH2:21][CH2:22][C:23]([C:37]#[N:38])([CH:34]([CH3:36])[CH3:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)[CH:6]([N+:18]([O-:20])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)(=O)C.[BH4-].[Na+].Cl.O>C(O)(C)C>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH2:7][CH:6]([N+:18]([O-:20])=[O:19])[CH2:5][CH2:21][CH2:22][C:23]([C:37]#[N:38])([CH:34]([CH3:36])[CH3:35])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(CC(C(CCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)OC(C)=O)[N+](=O)[O-])cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
The reaction mixture containing 1-(3,4-dimethoxyphenyl)-2-nitro-3-acetoxy-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (9) prepared in Preparation 7(A) was cooled to room temperature and diluted with isopropanol (350 mL). Solid NaBH4 (15 g, 0.4 mol) was added over 15 minutes at 25° C. The mixture was then heated to reflux (about 40° C.) for 15 hours, then cooled to 5° C. A solution of 10% HCl (30 mL) was slowly added, followed by water (100 mL). The organic layer was extracted, washed with saturated aqueous NH4Cl (200 mL), and saturated aqueous NaHCO3 (200 mL). The organic layer was evaporated to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (10, 58.7 g, m.p. 107°-110° C., MS m/e 470(M+)) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:8][C:6]1[CH:7]=[C:2]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([F:37])([F:38])[F:36])=[C:29]([Cl:28])[CH:30]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: Clc1cc(Cl)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a solution of CH3CN and water (75:25 mL) that has been degassed by bubbling N2 into the solvent was added 4,6-dichloro-pyrimidine (3.63 g, 22.7 mmol) and Ph3P (840 mg, 2.20 mmol). De-gassing was continued for an additional 15 min before adding 3-chloro-4-trifluoromethylphenyl boronic acid (5 g, 22 mmol), Pd(OAc)2 (250 mg, 1.11 mmol) and K3PO4 (9.4 g, 44.3 mmol). The resulting mixture was stirred at rt for 2 h before diluting with water and extracting with EtOAc. The organic layer was dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (2.3 g, 35%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2>CCOCC.[BH4-].[Zn+2].[BH4-]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Product: Fc1ccc2c(c1)CCN2
Reaction time: 48 h
Yield: 102.1 %

Procedure:
A solution of 6.8 grams (0.05 moles) of 5-fluoro-1H-indole in 50 ml of ether was cooled to 0° C. under nitrogen. 507 ml of a 0.15M solution of zinc borohydride in ether was added dropwise. The reaction was allowed to stir for 48 hours. The reaction was quenched with dilute hydrochloric acid. The pH was adjusted to 8.0 with dilute sodium hydroxide. The ether layer was seperated, dried and evaporated to give 7 grams of the titled compound.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH2:4][CH2:3][C:2]1=[O:11].O1CCOCC1>[Pd].C(O)C>[NH:1]1[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: O=C1CCC2=C(CCCC2)N1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1CC[C@@H]2CCCC[C@@H]2N1
Yield: 50.3 %

Procedure:
A suspension of 1 g of 3,4,5,6,7,8-hexahydro-2(1H)-quinolinone in 1:1 mixture of dioxane and ethanol was hydrogenated in presence of 250 mg of 10% palladium on carbon at 60 psi and room temperature for 4 hours. The catalyst was filtered on a bed of filter cell and washed with dioxane-ethanol mixture. The filtrate was concentrated to give a residue which was purified on silica gel using ethyl acetate as solvent to give 510 mg of the desired product containing about 10% trans-isomer. Recrystallization from hexane did not improve the isomer ratio.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:14][CH2:13][C:12]1[CH:18]=[CH:19][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:10][CH:11]=1
Reactant: CCOC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 73.5 %

Procedure:
To a stirred solution of ethyl 6-(tert-butoxycarbonylamino)nicotinate (100; 10.0 g, 27.3 mmol) in THF (40 mL) was added LiAlH4 (1.92 g, 50.5 mmol) in THF (60 mL) over a period of 30 min at 0° C. The resulting reaction mixture was stirred at 0° C. for 6 h. The reaction was then quenched by carefully adding water (1.0 ml) and 10% NaOH solution (2.0 mL) at 0° C. The resulting mixture was filtered and the filtrate was dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (dichloromethane:methanol=40:1) to afford tert-butyl 5-(hydroxymethyl)pyridin-2-ylcarbamate 101 (4.50 g, 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([N:14]=[C:15]=[O:16])=[O:13]>>[Cl:9][C:10]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:11]=1[C:12]([NH:14][C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:16])=[O:13]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Cl)cn1
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Cl)cn1

Procedure:
reacting 2-amino-5-chloropyridine with an equimolar amount of 2,6-dichlorobenzoyl isocyanate in a non-reactive organic solvent to obtain 1-(2,6-dichlorobenzoyl)-3-(5-chloro-2-pyridinyl)urea and,
Reaction SMILES: CCOCC.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[OH:16][NH:17][C:18](=N)[CH:19]([CH3:21])[CH3:20].Cl>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].C(O)C>[CH3:20][CH:19]([C:18]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][OH:6])[CH2:9][CH2:10]2)[O:16][N:17]=1)[CH3:21]
Reactant: CC(C)C(=N)NO
Reactant: N#CN1CCC(CO)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)c1noc(N2CCC(CO)CC2)n1
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
A solution of 1N ZnCl2 in Et2O (60.7 mL, 60.7 mmol) was added dropwise over 15 min to a solution of 4-(hydroxymethyl)-1-piperidinecarbonitrile (7.09 g, 50.6 mmol) and N-hydroxy-2-methylpropanimidamide (6.2 g, 60.7 mmol) in EtOAc (150 mL) at ambient temperature. The reaction mixture was left at ambient temperature for 15 min, decanted, and triturated with Et2O to give a white solid. The solid was heated in a solution of concentrated HCl (15 mL) and ethanol (30 mL) for 1 h. Ethanol was removed in vacuo, and the resulting residue was charged with water (150 mL). The mixture was neutralized with Na2CO3, and extracted with CH2Cl2. The organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 100% EtOAc/hexane to give 4.44 g (39%) of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol as a clear oil. 1H NMR (400 MHz, CDCl3): δ 4.20-4.10 (m, 2H), 3.51 (d, 2H, J=6.4 Hz), 3.07-2.97 (m, 2H), 2.90-2.75 (m, 1H), 1.85-1.75 (m, 2H), 1.76-1.62 (m, 1H), 1.36-1.19 (m, 8H); LRMS (ESI), m/z 226 (M+H).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[C:49]([C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[O:55][CH2:56][CH:57]([OH:60])[CH2:58][NH-:59])(=[O:51])[NH2:50].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:49]([C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[O:55][CH2:56][CH:57]([OH:60])[CH2:58][NH-:59])(=[O:51])[NH2:50]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CC(O)COc1cccc(C(N)=O)c1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 77 mg of Z-Phe-His-OH, 37 mg of H-Leu-Val-3-(m-carbamoylphenoxy)- 2-hydroxypropyl amide, 27 mg of HOBt and 36 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B7). Rf (B7)=0.15, Rf (N12)=0.30.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl>>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCOC1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of tetrahydrofuran-3-ol (500 mg, 5.68 mmol) in Py (5 ml), 4-methylbenzene-1-sulfonyl chloride (1623 mg, 8.51 mmol) was added, and the mixture and stirred at Rt for 1 hour. The mixture was poured into HCl 1M and extracted with AcOEt (2×). The organic phase was dried over Na2SO4 and evaporated under reduced pressure to give 350 mg of the title compound (26% yield).