Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]2[CH2:7][CH2:8][CH2:9][C@H:10]([N:11]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]([NH:34][C:35]([C:37]5[N:38]=[C:39]([CH:42]6[CH2:44][CH2:43]6)[O:40][CH:41]=5)=[O:36])=[C:16]([N:21]5[CH2:26][CH2:25][N:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])[CH2:23][CH2:22]5)[CH:17]=4)[C:12]3=[O:45])[C@H:4]2[O:3]1.Cl>CO.ClCCl>[OH:3][C@H:4]1[C@@H:5]([OH:6])[CH2:7][CH2:8][CH2:9][C@@H:10]1[N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([NH:34][C:35]([C:37]3[N:38]=[C:39]([CH:42]4[CH2:43][CH2:44]4)[O:40][CH:41]=3)=[O:36])=[C:16]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:17]=2)[C:12]1=[O:45]
Reactant: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2coc(C4CC4)n2)C(=O)N([C@H]2CCC[C@@H]4OC(C)(C)O[C@@H]42)CC3)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1ccccc1N1CCN(c2cc3c(cc2NC(=O)c2coc(C4CC4)n2)C(=O)N([C@H]2CCC[C@H](O)[C@@H]2O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-cyclopropyl-oxazole-4-carboxylic acid [(S)-2-((3aR,7aS)-2,2-dimethyl-hexahydro-benzo[1,3]dioxol-4-yl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide (0.165 g, 0.26 mmol) in anhydrous methanol (2 mL) was added methanolic HCl (5 mL) at 0° C. under N2 atmosphere. The reaction mixture was allowed to stir at room temperature for 1 h. The progress of the reaction was monitored by the TLC. Upon completion of the reaction, the reaction mixture was concentrated in vacuo, residue obtained was diluted with dichloromethane (100 mL); and was washed with 10% NaHCO3 solution, water followed by brine solution and dried over anhydrous Na2SO4. The crude product obtained was purified by the flash column chromatography (230-400 size mesh) by eluting 3.25-3.5% methanol in dichloromethane to afford the title compound. Finally, the title compound 2-cyclopropyl-oxazole-4-carboxylic acid [(S)-2-((2R,3S)-2,3-dihydroxy-cyclohexyl)-1-oxo-6-(4-o-tolyl-piperazin-1-yl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-amide was purified again by preparative HPLC to afford the pure compound. Yield (0.110 g, 65%, off white solid).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:27][C:9]2[NH:10][C:11]([C:22]([O:24]CC)=[O:23])=[C:12]([C:13](=[O:21])[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:8]=2[C:7]=1[CH3:28])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[S:27][C:9]2[NH:10][C:11]([C:22]([OH:24])=[O:23])=[C:12]([C:13](=[O:21])[C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[C:8]=2[C:7]=1[CH3:28])([OH:5])=[O:3]
Reactant: CCOC(=O)c1[nH]c2sc(C(=O)OCC)c(C)c2c1C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)sc2[nH]c(C(=O)O)c(C(=O)c3ccc(Cl)cc3)c12
Yield: 101.1 %

Procedure:
105 g of crude 2,5-diethoxycarbonyl-3-methyl-4-parachlorobenzoylthieno[2,3-b]pyrrole are heated at reflux in a mixture of 1 liter of ethanol and 1 liter of a normal solution of sodium hydroxide until complete saponification. The ethanol is then eliminated by distillation on a water bath. The aqueous solution is filtered and then acidified. The resulting precipitate is collected by filtration, washed with water, and dried with air and then in vacuo. In this manner, 92 g of crude 2,5-dicarboxy-3-methyl-4-parachlorobenzoylthieno[2,3-b]pyrrole are obtained, which is used in subsequent syntheses without further purification. The following were obtained in the same manner:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C\C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of maleic acid (0.58 g) in absolute ethanol (35 ml) with stirring at room temperature. The mixture is stirred for 3 hours at room temperature and concentrated at vacuum to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[C:19]=4[S:20][C:3]=1[C:4]=23.Br>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:19]=4[S:20][C:3]=1[C:4]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(OC)cccc1-2
Agent: Br
Product: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(O)cccc1-2

Procedure:
Reaction of 5-amino-N,N-diethyl-7-methoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine with 48% HBr as described in Example 64 gave the product.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][N:18]([CH2:20][CH:21]=[CH2:22])[CH3:19])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([N:18]([CH3:19])[CH2:17][C:16]#[C:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]1)[CH:21]=[CH2:22]
Reactant: C=CCN(C)CC#C[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C)CC#C[C@H]1CC[C@H](NC)CC1
Reaction time: 0.5 h

Procedure:
A solution of 200 mg (0.62 mmol) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester in 3.5 ml CH2Cl2 was treated at 0° C. with 1.7 ml TFA (for 20 min). After 30 min at this temperature, the reaction mixture was evaporated, treated with 1 N NaOH/CH2Cl2 (3×). The organic phase was dried over Na2SO4 and evaporated to yield 147 mg (quantitative) of trans-{4-[3-(Allyl-methyl-amino)-prop-1-ynyl]-cyclohexyl}-methyl-amine, MS: 221 (MH+).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:53][C@H:54]([C:58]([N:60]1[CH2:71][CH2:70][CH2:69][C@H:61]1[C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[O:59])[CH:55]([CH3:57])[CH3:56].Cl.C(N(CC)CC)C>ClCCl>[NH:1]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:53][C@H:54]([C:58]([N:60]1[CH2:71][CH2:70][CH2:69][C@H:61]1[C:62]([O:64][C:65]([CH3:66])([CH3:68])[CH3:67])=[O:63])=[O:59])[CH:55]([CH3:57])[CH3:56])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A solution of Z-Val-Pro-OH (681.3 mg, 1.95 mmol) in dichloromethane (6 mL), was successively treated at room temperature. with (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniun hexafluorophale (BOP) (865.1 mg, 1.95 mmol), H-Val-Pro-OtBu.HCl (500 mg, 1.63 mmol) and triethylamine (TEA) (500 μL, 3.58 mmol). The mixture was stirred overnight at room temperature. Then, the solvent was evaporated, the residue was dissolved in dichloromethane and washed with citric acid (10%), NaHCO3 (10%) and brine. The organic layer was dried (Na2SO4) and evaporated to dryness leaving a residue that was purified on a column chromatography with hexane-ethyl acetate, 2:1 to give X (68% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C[O-].[Na+].[F:13][C:14]([F:28])([F:27])[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O.C1(C)C=CC=CC=1>CO>[F:13][C:14]([F:28])([F:27])[CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1cccc(OCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
EX-659A) 3-Hydroxybenzaldehyde (12.22 g, 0.10 mol) and 100 mL of anhydrous methanol were combined in a 250 mL round-bottom flask. Sodium methoxide was slowly added as a 25 wt. % solution in methanol (21.61 g, 0.10 by mol), and the methanol was removed under vacuum. Then 2,2,2-trifluoroethyl-p-toluenesulfonate (25.42 g, 0.10 mol) was added, the flask was purged with nitrogen, and 100 mL of N-methyl pyrrolidine was added. The solution was stirred for 24 h at 90° C., quenched with water, and extracted with ether (3×). The combined ether layers were washed with 1 M NaOH (2×), water, and brine, dried over MgSO4, filtered, and evaporated to give 11.72 g of crude product Chromatography over silica gel eluting with 0-10% ethyl acetate in hexane followed by a second chromatography with toluene gave 5.24 g (26%) of the desired 3-(2,2,2-trifluoroethoxy)benzaldehyde product as a pale oil. 1H NMR (C6D6) δ9.61 (s, 1H), 7.14 (d, 1H), 7.06 (s, 1H), 6.97 (t, 1H), 6.75 (m, 1H), 3.75 (m, 2H). 19F NMR (C6D6) δ−74.45 (t, 3F).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]([O:13][CH2:14][C:15]#[N:16])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].CC[O:25]CC>>[F:1][C:2]([F:21])([F:22])[C:3]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]([O:13][CH2:14][C:15]([NH2:16])=[O:25])=[C:11]([CH3:20])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC#N
Reactant: CCOCC
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(N)=O

Procedure:
Stir a sample of crude 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetonitrile, prepared as described in Example 8a, with ether for 30 minutes. Filter the solid and recrystallize from ether to obtain as a white solid, 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetamide, m.p. 180°-182° C.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:96]=[CH:95][C:18]([C:19]([NH:21][CH:22]([C:92]([OH:94])=[O:93])[CH2:23][CH2:24][C:25](=[O:91])[NH:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]4[C:44](=[O:45])[C:43](=[O:46])[C:42]=4[NH:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][NH:83]C(=O)OC(C)(C)C)=[O:20])=[CH:17][CH:16]=3)[N:8]=2)[N:3]=1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH:22]([C:92]([OH:94])=[O:93])[CH2:23][CH2:24][C:25](=[O:91])[NH:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]4[C:44](=[O:45])[C:43](=[O:46])[C:42]=4[NH:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][NH2:83])=[O:20])=[CH:95][CH:96]=3)[N:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1c(NCCCOCCOCCOCCCNC(=O)CCC(NC(=O)c2ccc(NCc3cnc4nc(N)[nH]c(=O)c4n3)cc2)C(=O)O)c(=O)c1=O
Solvent: O=C(O)C(F)(F)F
Product: NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNc1c(NCCCOCCOCCOCCCNC(=O)CCC(NC(=O)c2ccc(NCc3cnc4nc(N)[nH]c(=O)c4n3)cc2)C(=O)O)c(=O)c1=O

Procedure:
0.3 g of 18-[(4-{[(2-amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-1-({2-[(39,39-dimethyl-37-oxo-3,6,9,12,15,18,21,24,27,30,33,38-dodecaoxa-36-azatetracont-1-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-15-oxo-4,7,10-trioxa-14-azanonadecan-19-oic acid is solubilized in 0.3 ml of trifluoroacetic acid.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na].[CH2:15](Br)[CH:16]=[CH2:17]>CO>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH2:17][CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: COC(=O)CC(=O)c1cccnc1
Agent: [Na]
Solvent: CO
Product: C=CCC(C(=O)OC)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(nicotinoyl)acetate (17.9 g, prepared by the method of E Wenkert et al, J. Org. Chem., 1983, 48, 5006) was added under argon to a solution of sodium metal (2.3 g) in methanol (200 ml) and the resulting mixture was stirred at 25° C. for 30 mins. Allyl bromide (12.0 g) was then added and stirring was continued overnight. A further amount (about 2 g) of allyl bromide was added, the mixture was stirred for 48 hours, and then concentrated. The residual oil was partitioned between water and ether and the aqueous layer was extracted three times with ether. The combined extracts were washed with saturated brine, dried (MgSO4) and concentrated. The residue was purified by flash column chromatography, eluting with a mixture of petroleum ether (b.p. 60°-80°) and ethyl acetate (1:1, v/v) to give methyl-2-nicotinoyl-4-pentenoate (A) as a pale yellow oil (13.8 g); NMR 2.6-2.9 (2H,m), 3.7 (3H,s), 4.4 (1H,m), 4.9-5.2 (2H,m), 5.5-6.0 (1H,m), 7.2-7.5 (1H,m), 8.1-8.3 (1H,m), 8.7-8.8 (1H,m) and 9.1-9.2 (1H,m).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C@@H:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([O:24][C:25](=[O:29])[C:26]#[C:27][CH3:28])[CH3:23]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:22]([O:24][C:25](=[O:29])/[CH:26]=[C:27](/[O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:15])([CH3:1])[O:6]2)=[CH:9][CH:10]=1)\[CH3:28])[CH3:23]
Reactant: CC1(C)OC[C@H](Cc2ccc(O)cc2)O1
Reactant: CC#CC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(C[C@H]2COC(C)(C)O2)cc1
Temperature: 80 °C
Yield: 6.9 %

Procedure:
A mixture of 4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenol (0.696 g, 3.34 mol), potassium carbonate (0.463 g, 0.003 mol), ethyl-2-butynoate (2.25 g, 0.020 mol) and a catalytic amount of 4-dimethylaminopyridine in tetrahydrofuran (15 mL) was placed in a sealed tube and heated at 80° C. for 6 h. The reaction mixture was cooled, filtered and the isolated solids washed with tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) which afforded (E)-3-[4-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-phenoxy]-but-2-enoic acid ethyl ester (0.440 g, 41%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:37][CH:38]([F:41])[CH2:39]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH:24][C:25](=[O:27])[CH3:26])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:39][CH:38]([F:41])[F:37])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:29][CH2:30][C:31]2([CH3:36])[CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)N[C@@H](Cc1cccc(O)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1cccc(OCC(F)F)c1)[C@H](O)[C@H]1CO[C@@H](OCC2(C)CCCC2)CN1C(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
Dissolve (2R,5R)-5-[(1S,2S)-2-acetylamino-1-hydroxy-3-(3-hydroxyphenyl)-propyl]-2-(1-methylcyclopentylmethoxy)-morpholine-4-carboxylic acid tert-butyl ester (204 mg) and 2,2-difluoro-1-bromoethane (0.065 mL) and cesium carbonate (391 mg) in N,N-dimethylformamide (5 mL) and heat to 60° C. for 18 hours. Dilute with ethyl acetate, wash with saturated aqueous sodium chloride, dry and purify (silica gel chromatography, eluting with 1:1 ethyl acetate:dichloromethane), to give the desired compound (223 mg).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Cl:6][C:7]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:13]=2)[N:8]=1>C1COCC1>[Cl:6][C:7]1[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([Cl:23])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)([OH:25])[CH:1]([CH3:3])[CH3:2])[CH:13]=2)[N:8]=1
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1)c1cncn1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 0.056 mL, 0.11 mmol) was added dropwise to a solution of (2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (35 mg, 0.092 mmol, Intermediate 2: step b) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes, then the ice bath was removed and the mixture was stirred for 25 minutes. The reaction was quenched by the addition of saturated aqueous NH4Cl and was diluted with water. The mixture was extracted three times with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated to dryness. The residue was purified by RP-HPLC (10-90% CH3CN—H2O, 0.1% TFA), then was converted to the free base (saturated aqueous NaHCO3/DCM extraction) and re-purified by flash column chromatography (silica gel, 25-70% acetone-EtOAc) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.99 (d, J=8.80 Hz, 1H), 7.62 (d, J=8.80 Hz, 1H), 7.46-7.57 (m, 3H), 7.32-7.39 (m, 2H), 7.28-7.32 (m, 1H), 7.18-7.25 (m, 1H), 3.29 (s, 3H), 2.65-2.76 (m, 1H), 1.24 (d, J=6.60 Hz, 3H), 0.72 (d, J=6.85 Hz, 3H); MS m/e 426.1 (M+H)+.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([CH3:28])[C:23]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:22]4)[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)cc(CCC(=O)O)n4C)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
Sodium hydroxide (57 mg) was added to a solution of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoate (E113) (67 mg) in THF (5 mL), isopropanol (5 mL) and water (2.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-2-yl]propanoic acid (E88) (1 mg). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.71 (2H, t), 3.02 (2H, t), 3.75 (3H, s), 4.88 (1H, m), 6.40 (1H, s), 7.44 (1H, d), 7.59 (1H, d), 7.81 (1H, dd), 8.11 (1H, dd), 8.18 (1H, d), 8.24 (1H, d), 12.33 (1H, br); MS (ES): C23H22ClN3O4 requires 439; found 440.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].CCN(C(C)C)C(C)C>Cl[Pd]Cl.CN(C)C=O>[F:10][C:4]1[CH:3]=[C:2](/[CH:13]=[CH:12]\[C:11]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[C:6]([F:8])[C:5]=1[OH:9]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C\c1cc(F)c(O)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2,6-difluorophenol (6.3 g, 30.15 mmol, 1.00 equiv), ethyl prop-2-enoate (17.2 g, 171.80 mmol, 5.70 equiv), P(toly)3 (18.24 g), DIEA (11.6 g, 89.76 mmol, 2.98 equiv), PdCl2 (0.531 g), N,N-dimethylformamide (100 mL). The resulting solution was stirred overnight at 80° C. The reaction was then quenched by the addition of 30 mL water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6 g (79%) of ethyl (2Z)-3-(3,5-difluoro-4-hydroxyphenyl)prop-2-enoate as yellow oil. Mass spectrum (ESI, m/z): Calcd. for C11H10F2O3, 229.1 (M+H). found 229.1
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:64]=[C:63]3[C:59]([CH2:60][N:61]([C@@H:66]([CH:71]([CH3:73])[CH3:72])[C:67]([O:69]C)=[O:68])[C:62]3=[O:65])=[CH:58][CH:57]=2)=[CH:52][C:51]=1[F:74])=[O:48]>>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:64]=[C:63]3[C:59]([CH2:60][N:61]([C@@H:66]([CH:71]([CH3:72])[CH3:73])[C:67]([OH:69])=[O:68])[C:62]3=[O:65])=[CH:58][CH:57]=2)=[CH:52][C:51]=1[F:74])=[O:48]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5ccccc5c4)c(F)c3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5ccccc5c4)c(F)c3)cc2C1=O
Yield: 69 %

Procedure:
The compound of example 450 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 449.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:37]([C:28]1[CH:29]=[CH:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=1)=[O:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 2-naphthoyl chloride (112 mg, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under-reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (160 mg, 82%).