Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[Cl-].[Ca+2].[Cl-].N1C=CC=CC=1.[S:22](Cl)(Cl)(=[O:24])=[O:23]>C(Cl)Cl>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][N:4]1[CH2:3][CH2:2][O:1][S:22]1(=[O:24])=[O:23]
Reactant: OCCNCc1ccccc1Cl
Reactant: O=S(=O)(Cl)Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1(=O)OCCN1Cc1ccccc1Cl
Temperature: -50 °C
Yield: 18.5 %

Procedure:
To a solution of N-hydroxyethyl-2-chlorobenzylamine (1.86g, 10.0mmole) in dry methylene chloride (6ml) in a reaction vessel fitted with a calcium chloride (CaCl2) drying tube was added dry pyridine (1.66ml, 20.5mmole). The solution was stirred and cooled to -50° C. Sulfuryl chloride (1.35g, 10.0mmole) dissolved in dry methylene chloride (4ml) was added dropwise over 20 minutes while the temperature of the solution was maintained between -45° C. and -50° C. The solution was stirred at -50° C. for 90 minutes and then allowed to warm to 8° C over 90 minutes. The entire reaction mixture was poured onto a silica gel bed (30g), slurry-packed in a 60ml Type "C" sintered glass funnel. The bed was eluted with methylene chloride while collecting 40ml fractions. Fractions containing the product were combined and the solvent removed by evaporation under vacuum at 40° C. yielding N-(2-chlorobenzyl)- 2,2-dioxo-1,2,3-oxathiazolidine as a clear oil (0.40g, 1.85mmole), which crystallized. Characteristic analytical data are mp. 61°-62.5° C.; and NMR spectra similar to those of Example 2A (above).
Reaction SMILES: C(OC(=O)[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:45])[C:21]([O:37]CC3C=CC=CC=3)=[C:22]([C:24]3[O:25][C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:27][N:28]=3)[N:23]=[C:12]21)C1C=CC=CC=1.Br.C(O)(=O)C>C(Cl)Cl>[NH2:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:45])[C:21]([OH:37])=[C:22]([C:24]3[O:25][C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:27][N:28]=3)[N:23]=[C:12]21
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC12CCC(CC1)Cn1c2nc(-c2nnc(Cc3ccc(F)cc3)o2)c(O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
To a mixture of benzyl(3-(benzyloxy)-2-(5-(4-fluorobenzyl)-1,3,4-oxadiazol-2-yl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 11 (30 mg, 0.048 mmol) in CH2Cl2 (2 mL) was added HBr in acetic acid (0.218 mL, 1.206 mmol) and the mixture stirred at room temperature for 16 h. The mixture was concentrated and dried under high vacuum to afford the title compound (18 mg, 0.038 mmol, 78% yield) as a brown solid. 1H NMR (500 MHz, MeOD) δ ppm 7.39-7.46 (2H, m), 7.08-7.14 (2H, m), 4.38 (2H, s), 4.20 (2H, d, J=3.66 Hz), 2.60 (1H, br. s.), 2.22-2.31 (2H, m), 2.05-2.18 (4H, m), 1.85-1.94 (2H, m). LCMS (M+H)=398.18.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[CH3:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:33]2[CH:34]=[N:35][C:30]([CH3:29])=[CH:31][CH:32]=2)[CH2:23]1
Reactant: Cc1ccc(B(O)O)cn1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)ccc2N2C[C@H](O)[C@@H](O)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using 3-bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 7.1) and (6-methylpyridin-3-yl)boronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.65 min, m/z=474.0 [M+H]+, m/z=472.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.53 (s, 3H) 2.74 (d, J=10.76 Hz, 2H) 3.25 (dd, J=10.51, 3.67 Hz, 2H) 3.85 (br. s, 2H) 5.03 (br. s, 2H) 6.90 (d, J=8.80 Hz, 1H) 7.27-7.38 (m, 3H) 7.68 (dd, J=7.82, 2.20 Hz, 1H) 7.77 (d, J=2.20 Hz, 1H) 7.85-7.88 (m, 2H) 7.87-7.91 (m, 1H) 8.48 (d, J=2.20 Hz, 1H) 10.09 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(F)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of methyl 3-[4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]-5-fluoropyridin-2-yl]propionate (150 mg, 0.310 mmol) in a mixture of methanol (2 ml) and tetrahydrofuran (2 ml) was added a 1N aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was made weakly acidic by the addition of 1N hydrochloric acid, followed by extraction with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (145 mg, 0.310 mmol, quant.) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.Cl.O>CO.[OH-].[Na+]>[N+:24]([C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)nc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
6-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]nicotinic acid methyl ester (10 g) was dissolved in methanol (75 ml) and with the addition of aqueous 1N-sodium hydroxide (75 ml), the mixture was stirred at 30° C for 2 hours. With the slow addition of 3N-hydrochloric acid for neutralization (pH=˜5), water (110 ml) was slowly added to the mixture for precipitate. After 2-hours stirring, the precipitate was filtered, washed with water and dried to give a desired compound of 8.66 g (yield: 90%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[S:27][N:26]=[C:25]([Cl:28])[N:24]=1)=[O:4].[OH-].[Li+]>>[Cl:28][C:25]1[N:24]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:21])([F:22])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[S:27][N:26]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nc(Cl)ns1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1nc(Cl)ns1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-(3-chloro-[1,2,4]thiadiazol-5-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as brown solid. MS (ESI): m/z=442.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:23][C:22]=2[CH:34]=1.[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.O1CCCC1.C(Cl)(Cl)Cl>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:25]([C:7]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)=[O:9])=[C:24]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[S:23][C:22]=2[CH:34]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
4-Methoxybenzoic acid (450 mg, 2.96 mmol), thionyl chloride (3 ml, 44.4 mmol) and anhydrous dimethylformamide (1 drop) were added to anhydrous chloroform (10 ml), and the resulting mixture was refluxed for 3 hours under argon atmosphere and then cooled to room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in anhydrous dichloromethane, and 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (760 mg, 2.8 mmol) synthesized by the method described in J. Med. Chem. 1057(1984) and aluminum chloride (2.37 g, 17.76 mmol) were added to the resulting solution followed by stirring for 4 hours at room temperature. Tetrahydrofuran and ice were added to stop the reaction and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane=1/1) to give [6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-methoxy-phenyl)-methanone (405 mg, Yield 39%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([I:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[F:1]
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 96 %

Procedure:
2-Fluoro-5-iodo-3-nitro-benzoic acid (2.0 g, 6.43 mmol) and SOCl2 (918 mg, 7.72 mmol) were added to 20 mL MeOH, and the mixture was refluxed for two hours and then cooled to room temperature. Solvent was evaporated under reduced pressure and the residue was dissolved in EtOAa. The EtOAc slolution was washed with brine, dried over NasSO4, filtered and concentrated under reduced pressure to give 2.0 g (96%) of 2-fluoro-5-iodo-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([O:4][C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:24]([N:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])[NH:13][C:14](OCC1C=CC=CC=1)=O)=[O:6])[CH3:3].N1CCC[C@H]1C(OC(C)(C)C)=O.ClC[C:53](=[O:71])[C@@H:54]([NH:62][C:63](=[O:70])[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(=O)(O)[O-].[Na+]>C(O)C.[Pd].CN(C)C=O>[C:63]([NH:62][CH:54]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:53](=[O:71])[CH2:14][NH:13][C@H:12]([C:24]([N:26]1[CH2:37][CH2:36][CH2:35][C@H:27]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:25])[CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5]([O:4][C:2]([CH3:1])([CH3:38])[CH3:3])=[O:6])(=[O:70])[C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: O=C([O-])O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NCC(=O)C(Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester product from part (a) is reduced in ethanol with palladium on carbon catalyst (10%) to yield 3.99 g. of 1-[N6 -[1,1-dimethylethoxy)carbonyl]-L-lysyl]L-proline, 1,1-dimethylethyl ester. This material is taken into 40 ml. of dimethylformamide and treated with (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide (3.01 g.), from Example 63(b), and sodium bicarbonate (840 mg.). After stirring for 18 hours at room temperature, the reaction mixture is concentrated in vacuo, taken into ethyl acetate and washed with saturated sodium bicarbonate. The crude product (7.0 g.) is purified on a silica gel column eluting with ethyl acetate:1% methanol to give 1.7 g. of (S)-1-[N2 -[3-benzoylamino)-2-oxo-4-phenylbutyl]-N6 -[(1,1-dimethylethoxy)carbonyl]-L-lysyl]-L-proline, 1,1-dimethylethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12]([CH3:22])=[CH:13][CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19])=[C:5]([CH3:23])[C:4]=1[CH3:24].[CH2:25]([NH:27]CC)[CH3:26]>>[CH2:25]([NH:27][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH:15]=[CH:14][CH:13]=[C:12]([CH3:22])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:24])[C:5]=1[CH3:23])[CH3:26]
Reactant: CCNCC
Reactant: COc1cc(C)c(C=CC(C)=CC=CC(C)=CC(=O)Cl)c(C)c1C
Product: CCNC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
9-(4-methoxy-2,3,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid chloride and diethylamine are converted to
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[C:14]([CH3:20])[C:13]=2[CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:19])[CH3:18])=[C:14]([CH3:20])[C:13]=2[CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(C)O)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]ethanone (0.53 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (10 mL) and methanol (1 mL), and sodium borohydride (90%, 0.16 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (1 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.53 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16](N(CC)CC)[CH3:17].ICC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH2:16][CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC1(c2ccc(F)c(Cl)c2)CCNC1
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCN1CCC(OC)(c2ccc(F)c(Cl)c2)C1

Procedure:
Preparation according to Example 22. (−)-3-(3-chloro-4-fluorophenyl)-3-methoxypyrrolidine (0.01 g, 0.043 mmol), triethylamine (12.1 μL, 0.086 mmol), tetrahydrofuran (2 ml) and iodoethane (5.2 μL, 0.065 mmol). The crude product analyzed by GCMS. Analysis showed 83% conversion. MS m/z (relative intensity, 70 eV) 257 (M+, 4), 242 (34), 227 (20), 157 (32), 71 (bp).
Reaction SMILES: [O:1]1[C:5]2([C@@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[OH:27][C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(CC)CC>C1COCC1>[OH:27][C:28]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:29][CH2:30][CH:31]([N:7]2[CH2:8][C@H:9]([NH:10][C:11](=[O:26])[CH2:12][NH:13][C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[C:5]3([O:1][CH2:2][CH2:3][CH2:4]3)[CH2:6]2)[CH2:32][CH2:33]1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CNCC12CCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCC(O)(c3ccccc3)CC2)CC12CCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the amine of step H (90 mg, 0.243 mmol) and 4-hydroxy-4-phenyl-cyclohexanone (43 mg, 0.226 mmol) in THF (5 mL) was added sodium triacetoxyborohydride (129 mg, 0.61 mmol) followed by Et3N (0.29 ml, 2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed under vacuum. The residue was taken up in EtOAc/NaHCO3 aqueous solution. The two phases were separated and the water layer was extracted with EtOAc twice. The combined organic phase was dried (Na2SO4) and concentrated. Purification by prep-HPLC provided two isomers. MS: 546.4 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])=[CH2:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH2:5][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1Cl
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(CN1CCCC1)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)acrylic acid methyl ester (0.70 mmol) in 2 mL THF was added pyrrolidine (0.77 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 50 min, diluted with DCM and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired compound as pinkish oil;
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O[Li].O.Cl>C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:22][CH:23]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2ccc(CO)cc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C#Cc2ccc(CO)cc2)cc1
Reaction time: 1.5 h

Procedure:
Ethyl 2-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenoxy)acetate (54.0 mg, 0.174 mmol) was dissolved in THF (1 mL), and LiOH.H2O (10.9 mg, 0.261 mmol) in water (0.5 mL) was added. The mixture was stirred for 1.5 h. and 3% HCl (0.5 mL) was added until pH<1. Water (10 mL) was added, and the mixture was extracted with EtOAc (3×10 mL). The combined EtOAc phases was washed with brine (10 mL), dried over MgSO4, and concentrated under reduced pressure. The product was white/yellow and solid (48.0 mg, 98%). Rf=0.04 (EtOAc:hexanes 1:1 v/v). 1H-NMR (DMSO-d6): □ 4.52 (s, 2H, CH2OH); 4.73 (s, 2H, OCH2); 5.26 (s, 1H, CH2OH); 6.95 (d, 2H, J=8.7 Hz, Ph); 7.35 (d, 2H, J=7.8 Hz, Ph); 7.48 (m, 4H, Ph); 12.99 (s, 1H, COOH). 13C-NMR (DMSO-d6): □ 62.0 (CH2OH); 64.0 (OCH2); 87.7 (CC); 88.3 (CC); 114.3, 114.4, 120.3, 126.1, 130.5, 132.3, 142.6, 157.5 (Ph); 169.4 (COO). EI-MS: m/z calculated for C17H14O4 [M]+ 282; [C15H11O2]+ 223; [C8H8O3]+ 152. found 282, 223, 152.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:48]6[CH2:53]COC[CH2:49]6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].COC(NC(C1CCOCC1)C(O)=O)=O>>[CH3:58][O:57][C:55](=[O:56])[NH:54][CH:47]([C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:22]=[CH:21][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][C:11]([F:13])([F:14])[CH2:12][N:8]6[C:6](=[O:7])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:66])[C:60]6[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=6)=[N:19][CH:18]=5)=[CH:25][CH:24]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:59])[CH:48]([CH3:53])[CH3:49]
Reactant: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: COC(=O)NC(C(=O)O)C1CCOCC1
Product: COC(=O)NC(C(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Yield: 17 %

Procedure:
[1-(2-{5-[6-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.05 g, 17%) was prepared following the procedure for {2-[4,4-Difluoro-2-(5-{4-[6-(2-{1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyric acid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid. LCMS-ESI+: calc'd for C47H48F2N8O6: 858.37 (M+); Found: 859.92 (M+H+).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:55])[CH2:7][N:8]([CH2:49][C:50]([O:52]CC)=[O:51])[C:9](=[O:48])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:11]=1)C>>[C:6]([CH2:7][N:8]([C:9](=[O:48])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:13]=[C:12]([O:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:11]=1)[CH2:49][C:50]([OH:52])=[O:51])([OH:55])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCOc2ccc(OC)cc2)cc(C(=O)N(CC(=O)O)CC(=O)O)c1

Procedure:
Sodium hydroxide hydrolysis of N-(2-ethoxy-2-oxoethyl)-N-[3-[3-(4-methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine ethyl ester as in Example 11 gave N-(carboxymethyl)-N-[3-[3-(4-methoxyphenoxy)propoxy]-5-(octadecyloxy)benzoyl]glycine which gave nmr and mass spectra consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:12]Br>O>[Br:12][C:9]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][NH:7][CH:8]=1
Reactant: CC(C)(C)c1cc[nH]n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h

Procedure:
2.48 g of 3-t-butyl-1H-pyrazole was suspended in 35 ml of water, and 2.5 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 3.50 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.14 of 4-bromo-3-t-butyl-1H-pyrazole.