Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CC(O)=O.[Br:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][CH2:17][C:18](=O)[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:22]=[C:21]3[C:14]=2[CH:13]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Br:11][C:12]1[CH:31]=[CH:30][C:15]2[O:16][CH2:17][CH:18]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH2:19][N:20]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH:22]=[C:21]3[C:14]=2[CH:13]=1
Reactant: CN(C)CCN
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)CCNC1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N′,N′-dimethylethane-1,2-diamine (39 mg, 0.440 mmol) and CH3COOH (26 mg, 0.440 mmol) were added to the mixture of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (100 mg, 0.293 mmol) in 1,2-dichloroethane (2 mL). The mixture was stirred at room temperature for 20 minutes. Then NaBH(OAc)3 (93 mg, 0.440 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated NaHCO3 (30 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (dichloromethane:MeOH=1:1) to provide N1-(2-bromo-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-yl)-N2,N2-dimethylethane-1,2-diamine. 1H-NMR (CDCl3, 400 MHz) δ 7.51˜7.56 (m, 2H), 7.42 (s, 1H), 7.29˜7.32 (m, 1H), 7.16˜7.18 (m, 1H), 7.06 (t, J=7.2 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.56 (s, 1H), 3.86˜4.32 (m, 4H), 2.81˜3.03 (m, 5H), 2.59 (s, 6H). MS (M+H)+: 414/416.
Reaction SMILES: [CH3:1][OH:2].Cl[S:4]([N:7]=[C:8]=[O:9])(=[O:6])=[O:5].[NH2:10][C:11]1[C:12]([CH3:36])=[C:13]2[C:17](=[C:18]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]=1[CH3:20])[N:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][CH2:14]2>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][O:2][C:8]([NH:7][S:4]([NH:10][C:11]1[C:12]([CH3:36])=[C:13]2[C:17](=[C:18]([NH:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:26])[CH3:24])[C:19]=1[CH3:20])[N:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:15][CH2:14]2)(=[O:6])=[O:5])=[O:9]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CO
Reactant: CCCCCCCCN1CCc2c(C)c(N)c(C)c(NC(=O)C(C)(C)C)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCN1CCc2c(C)c(NS(=O)(=O)NC(=O)OC)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 0.33 h

Procedure:
Methanol (0.13 mL) was added to methylene chloride (2.6 mL) and chlorosulfonyl isocyanate (0.29 mL) was added at −20° C. The mixture was stirred at −20° C. to 10° C. for 20 min. N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide (612 mg) and triethylamine (0.46 mL) were added to the reaction mixture and the mixture was further stirred at −9° C. for 30 min. Methylene chloride was added to the reaction mixture, and the mixture was washed successively with 10% aqueous citric acid, saturated aqueous sodium hydrogencarbonate and saturated brine and dried over sodium sulfate. Methylene chloride was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as crystals. (601 mg).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[C:46]([O:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@@:54]1([CH3:61])[C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[C:46]([O:50][C:51]([N:53]1[CH2:60][CH2:59][CH2:58][C@@:54]1([CH3:61])[C:55]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:56])=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCN1C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirring solution of #114 (1.02 g, 1.61 mmol, 1.0 eq.) and 1-(tert-butoxycarbonyl)-2-methyl-L-proline (443 mg, 1.93 mmol, 1.2 eq.) in 12 mL of dichloromethane, HATU (735 mg, 1.93 mmol, 1.2 eq.) was added followed by Hunig's base (1.12 mL, 6.45 mmol, 4.0 eq.). The reaction was allowed to stir at room temperature for 2 hours. The reaction was reduced down, diluted with ethyl acetate before being washed with 0.5 N HCl and brine. Organics where then dried over sodium sulfate, reduced to a smaller volume, and then reduced down on silica. Silica chromatography was then performed (Gradient: 0%-45% acetone in heptanes) producing #116 (1.02 g, 74%) as a white solid. LC-MS (Protocol Q): m/z 844.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH3:20])[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([Cl:19])[CH:11]=3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(Cl)Cl>[Cl:19][C:12]1[CH:11]=[C:10]2[C:15]([C:16]([C:17]#[N:18])=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])[CH:7]=[N:6][CH:5]=3)[N:9]2[CH3:20])=[CH:14][CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(N)c2)c(C#N)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 211, 85 mg, 0.3 mmol) in DCM (15 mL) is added triethylamine (122 mg, 1.2 mmol) and ethanesulfonyl chloride (77 mg, 0.6 mmol) and the reaction mixture is stirred overnight. The solvent is removed and the residue is redissolved in methanol (15 mL). Aqueous 1M NaOH (1 mL) is added and the reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (methanol in dichloromethane gradient) to give ethanesulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-yl]-amide as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.3 Hz, 3H), 3.23-3.33 (m, 2H), 3.79 (s, 3H), 7.36 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.90 (t, J=2.3 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 8.61 (d, J=2.3 Hz, 2H), 10.43 (s, 1H). HRMS (ESI) m/z 375.0692 [(M+H)+ Calcd for C17H16ClN4O2S: 375.0682].
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH3:7][C:8]1[NH:9][C:10]([CH3:21])=[C:11]2[C:15]([CH3:18])([C:16]#[N:17])[CH2:14][C:13]([CH3:20])([CH3:19])[C:12]=12.Cl.Cl[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28]>O>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:9]1[C:10]([CH3:21])=[C:11]2[C:15]([CH3:18])([C:16]#[N:17])[CH2:14][C:13]([CH3:20])([CH3:19])[C:12]2=[C:8]1[CH3:7]
Reactant: Cc1[nH]c(C)c2c1C(C)(C)CC2(C)C#N
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c2c(c(C)n1CCCN(C)C)C(C)(C#N)CC2(C)C
Temperature: 15 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
To a solution prepared by heating 23.2 g. (0.55 mole) of a 67% mineral oil dispersion of sodium hydride in 200 ml. of anhydrous dimethylsulfoxide was added 50.5 g. (0.25 mole) of the 2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile described above in Example 3. The mixture was stirred under nitrogen for about two hours, cooled to 15° C., and treated with 39.5 g. (0.25 mole) of 3-chloro-N,N-dimethylpropylamine hydrochloride. When the foaming had subsided, the mixture was stirred at room temperature overnight, poured into water, and the gummy solid which separated was taken into diethyl ether and the solution washed first with water, then with saturated brine, dried and taken to dryness to give 69 g. of a solid which was recrystallized once from hexane and once from isopropanol to give 29 g of 2-[3-(di-methylamino)propyl]-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carbonitrile, m.p. 90.5°-91.0° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:7]2[C:8]([O:10]C(=O)[NH:12][C:6]2=[CH:5][CH:4]=1)=O.Cl.[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([NH2:24])[CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH3:16][O:17][C:18](=[O:25])[C@@H:19]([NH:24][C:8](=[O:10])[C:7]1[CH:14]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:12])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCC[C@H](NC(=O)c1cc(OC)ccc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.9 %

Procedure:
To a mixture of 5-methoxy-isatoic anhydride (1.0 g, 5.18 mmol) and (S)-2-amino-hexanoic acid methyl ester hydrochloride (1.4 g, 7.71 mmol) (prepared according to example A) in DMF (10 mL) is added triethylamine (2.0 mL, 11.48 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the residue is purified by flash chromatography with 60% EtOAc in Hexane as the eluent to afford (S)-2-(2-amino-5-methoxy-benzoylamino)-hexanoic acid methyl ester (410 mg, 27%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[O:6])[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:40])C=1>C1COCC1.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2[CH2:12][S:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:40])=[O:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)c2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(phenylsulfinyl)methyl]-1H-1,2,3-triazole-4-carboxamide (107 mg, 0.24 mmol) obtained in Example 313 was dissolved in THF (2.0 ml), m-chloroperbenzoic acid (purity 65%, 64 mg, 0.24 mmol, 1.0 eq.) was added with stirring at 0° C., and the mixture was stirred for 1 hr and at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (25 ml), washed with 5% aqueous sodium sulfite solution, 2% aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added to the residue, and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (111 mg, 0.24 mmol, quant.).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Li]CCCC.C1CCCCC1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>C1COCC1>[CH2:10]([O:9][C:3](=[O:8])[CH2:4][C:5](=[O:6])[CH2:7][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of NaH (60% suspension in mineral oil, 1.42 g, 36 mmol) in dry THF (50 mL) was added ethyl acetoacetate (4.3 g, 33 mmol) dropwise at 0° C. After 10 min stirring at this temperature, a 2.0 M solution of n-BuLi in cyclohexane (17.7 mL, 35 mmol) was added dropwise under N2. The stirring was continued at 0° C. for 10 min., 4-fluorobenzyl bromide (9.45 g, 50 mmol) was then added dropwise at 0° C. The resultant solution was allowed to warm to rt. After 20 min, the reaction as quenched with 2 N HCl/Et2O (20 mL/40 mL). Layers were separated, the aqueous layer was extracted with ether (3×50 mL). Combined ether solution was washed with H2O (50 mL), brine (50 mL), and dried with Na2SO4. After removal of the solvent under reduced pressure, the resultant oily material was purified by flush column chromatography on silica gel (hexane to 4:1 hexane/EtOAc). The corresponding intermediate 5-(4-Fluoro-phenyl)-3-oxo-pentanoic acid ethyl ester was obtained as a colorless liquid (7.16 g, 92%). 1H NMR (300 MHz, CDCl3) δ1.25 (t, 3H, J=7), 2.80-2.95 (m, 4H), 3.40 (s, 2H), 4.10-4.25 (m, 2H), 6.9-7.0 (m, 2H), 7.1-7.2 (m, 2H). ESMS calcd (C13H15FO3): 238.1; found: 239.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:16])[NH2:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)CC1

Procedure:
To a mixture of 1-benzyl-4-ethoxycarbonylpiperidine (6.88 g) and formamide (3.71 ml) in N,N-dimethylformamide (30 ml) was added 28% sodium methoxide solution in methanol (4.0 ml) at 100° C. under stirring. After stirring at 100° C. for 1 hour, the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine and dried over magnesium sulfate, and evaporated in vacuo. The residue was recrystallized from ether to give 1-benzyl-4-carbamoylpiperidine (2.8 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:4][OH:5])C.[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:9]([Cl:19])[N:8]=1.C(N(CC)CC)C.[OH2:27]>CN(C=O)C.CCOC(C)=O>[Cl:6][C:7]1[N:8]=[C:9]([Cl:19])[C:10]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])=[C:11]([NH:1][C@H:2]([OH:27])[CH2:4][OH:5])[N:12]=1
Reactant: C[C@@H](N)CO
Reactant: CN(C)C(=O)c1c(Cl)nc(Cl)nc1Cl
Reactant: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c(Cl)nc(Cl)nc1N[C@H](O)CO
Reaction time: 1 h

Procedure:
(R)-alaninol (0.46 g) in DMF (20 ml) was added dropwise to the subtitle product of step iii) (1.60 g) at −5° C. To this mixture was added triethylamine (0.63 g), the mixture allowed to come to room temperature and stirred for 1 h. To the mixture was added water (60 ml) and EtOAc (2×200 ml). The organic layer was washed With water (3×50 ml), brine (30 ml) and dried (MgSO4). The solid was filtered and the filtrate evaporated to dryness to give a yellow solid. This was chromatographed using EtOAc as eluent to yield the subtitle compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.C(O)(=O)C.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 3-bromo-4-fluorobenzaldehyde (50.0 g) in 1,2-dichloroethane (500 mL) is cooled to 0° C. Acetic acid (14.1 mL) and morpholine (23.6 mL) are added slowly, maintaining the temperature below 4° C. Sodium triacetoxyborohydride (78.3 g) is added all at once, maintaining the temperature below 5° C. The mixture is allowed to warm to rt and stirred for 18 hrs. The reaction is quenched with 1 N NaOH (200 mL) and extracted with CH2Cl2 (500 mL). The organic layer is washed with 1 N NaOH (2×200 mL). The aqueous layers are combined and back-extracted with CH2Cl2 (100 mL). The organic layers are combined and extracted with 0.5 N HCl (5×250 mL). The acidic aqueous layers are combined, and 2 N NaOH is added until the solution is basic (pH=12). The aqueous layer is then extracted with CH2Cl2 (6×100 mL). The organic layers are combined, dried (MgSO4) and concentrated in vacuo to a clear, colorless oil. The crude product is distilled (126° C., 0.3 Torr) to afford 48.9 g (72%) of the title compound as a clear, colorless oil. Physical characteristics: B.p. 126° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.62, 7.35-7.29, 3.56, 3.45, 2.34; 13C NMR (75 MHz, DMSO-d6) δ 157.3, 136.1, 133.3, 129.8, 116.2, 107.7, 66.1, 60.9, 53.0; IR (liq.) 2855, 2807, 1495, 1455, 1348, 1257, 1244, 1118, 1009, 862 cm−1; MS (ESI+) m/z 274 (M+H)+. Anal. Calcd for C11H13BrFNO: C, 48.20; H, 4.78; N, 5.11; Br, 29.15. Found: C, 48.04; H, 4.79; N, 5.11; Br, 28.18.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:19][CH2:20]OS(C)(=O)=O)[CH2:12][CH2:13]OS(C)(=O)=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[Br-].[Li+].[C:28](=[O:31])([O-])[O-].[K+].[K+].[C:34](#[N:36])[CH3:35]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:12][CH2:13][N:36]([CH:34]([CH3:35])[CH2:28][OH:31])[CH2:20][CH2:19]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC#N
Reactant: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cccc2c1OCCO2
Reactant: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Product: CC(CO)N1CCN(c2cccc3c2OCCO3)CC1
Temperature: 82 °C

Procedure:
Dimesylate III (67.0 g, 0.17 mol), D-alaminol (14.0 g, 0.19 mol), lithium bromide (31.0 g, 0.35 mol), and potassium carbonate (74.8 g, 0.54 mol) are mixed together with acetonitrile (750 mL). The resulting suspension is refluxed (82° C.) for 27 h with monitoring by HPLC. The reaction mixture is cooled, filtered, and insoluble residue washed with acetonitrile. Mother liquor is concentrated to a small volume, filtered through 200 cm3 of silica gel, and eluted with 1.5 L of MeOH 10% in EtOAc. After removing solvent on rotary evaporator, the residue is redissolved in EtOAc (200 mL). This solution is washed with water (2×50 mL), dried with MgSO4 and concentrated to produce IV as thick golden oil that slowly crystallizes upon standing; yield 29.4 g (63%) and purity 88.3 area % (LC-MS). Melting point=91–92° C. 1H NMR (CDCl3) δ 6.78 (t, J=7.5 Hz, 1H), 6.55 (m, 2H), 4.29 (m, 4H), 3.45 (dd, J=11, 5 Hz, 1H), 3.38 (t, J=11 Hz, 1H), 3.10 (br m, 4H), 2.86 (m, 3H), 2.63 (m, 2H), 0.96 (d, J=7.5 Hz, 3H).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][CH:17]=2)=[CH:12][CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:18][C:17]=2[Cl:8])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(Cl)c(-c2ccc(Br)cc2)[nH]1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
NCS (0.51 g, 3.82 mmol) was added to a solution of tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.55 mmol) in DMF (25 mL) and the mixture was heated at 50° C. overnight. The volatiles were removed under vacuum. The residue was purified by flash column chromatography (BIOTAGE®), eluting with a gradient of 0 to 10% EtOAc/DCM to afford the partially pure (S)-tert-butyl 2-(5-(4-bromophenyl)-4-chloro-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.04 g) as yellow foam. LC-MS retention time 1.99 min; m/z 427.12 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.63 (s, 4H), 4.74-4.81 (m, 1H), 3.64-3.72 (m, 1H), 3.45-3.55 (m, 1H), 2.27-2.42 (m, 1H), 2.00-2.15 (m, 2H), 1.90-2.00 (m, 1H), 1.48 (m, 3H), 1.27 (m, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26](NCC)[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[CH:35]([O:38]C1N=C(C(O)=O)C=C(C)N=1)([CH3:37])[CH3:36]>>[CH:35]([O:38][C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:18]=[C:3]([CH3:1])[C:4]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:15]([CH3:34])[CH:16]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)([CH3:37])[CH3:36]
Reactant: Cc1cc(C(=O)O)nc(OC(C)C)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)nc(OC(C)C)n1

Procedure:
rac-N-(3-{4-[5-(2-Isopropoxy-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-isopropoxy-6-methyl-pyrimidine-4-carboxylic acid and 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamimioyl)-2,6-dimethyl-phenoxy]-propyl}-acetamide; LC-MS: tR=0.95 min; [M+H]+=472.21.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N[C@H](C(O)=[O:23])CCCNC(=N)N>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:23])=[CH:6][CH:5]=1
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Phe 1.00(1); Arg 2.06(2);
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[O:23][C:24]=3[CH3:25])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.94 g), tetrahydrofuran (4 mL) and ethanol (4 mL) was added a 1N aqueous sodium hydroxide solution (3.6 mL) and the mixture was stirred at 50° C. for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.75 g, 85%) of 3-[2-ethoxy-4-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.