Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][C:7]=2[O:6]1>C(Cl)(Cl)(Cl)Cl>[CH2:5]1[O:15][C:14]2[CH:13]=[CH:12][C:9]([CH2:10][Br:2])=[CH:8][C:7]=2[O:6]1
Reactant: BrP(Br)Br
Reactant: OCc1ccc2c(c1)OCO2
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
Phosphorus tribromide (0.35 mmol) was added to a solution of 3,4-methylenedioxy benzyl alcohol (1 mmol) in 10 ml of carbon tetrachloride at room temperature. The reaction mixture was refluxed for 4 hrs., cooled to room temperature and washed with sodium carbonate solution (10 ml). The organic layer was dried and concentrated under reduced pressure to give the required product which was used as such for the next step.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][I:12]>O1CCOCC1>[I-:12].[CH3:11][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: CI
Solvent: C1COCCO1
Product: C[n+]1cccc2ccccc21
Product: [I-]
Temperature: 150 °C
Reaction time: 1 h

Procedure:
N-methylquinolinium iodide (Compound III) was synthesized according to the description in the aforementioned reference. Specifically, 2.4 mL of quinoline and 4 mL of methyl iodide were added to 42 mL of anhydrous dioxane, which was stirred at 150° C. for one hour. Thereafter, it was filtered and thereby a precipitate was collected and then washed with ether and petroleum ether. This was dried and thus N-methylquinolinium iodide (Compound III) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH2:9].[CH:10]1[N:15]=[C:14](Cl)[C:13]2[N:17]=[CH:18][N:19]([C@@H:20]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]3[OH:28])[C:12]=2[N:11]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:14]1[C:13]2[N:17]=[CH:18][N:19]([C:12]=2[N:11]=[CH:10][N:15]=1)[C@@H:20]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]1[OH:28]
Reactant: Cc1ccccc1CN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 60 °C

Procedure:
The title compound was prepared by reacting (2-methylphenyl)methylamine (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60° C. for 6 h, cooled, filtered and evaporated. The residue was purified by flash chromatography, eluting initially with dichloromethane, and later increasing polarity to dichloromethanethanol (9:1), to provide the product (2.6 g, 70%) as a solid which was recrystallised from methanol to give N-[(2-methylphenyl)methyl]adenosine as white crystals (1.75 g, 47%), mp 161.5°-163.5° C., 1H NMR (DMSO-d6)δ 2.35 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.65-3.72 (1H, m, H-5'b), 3.98 (1H, q, H-4'), 4.16 (1H, m, H-3'), 4.64 (1H, q, H-2'), 5.41 (1H, t, 5'-0H), 5.21, 5.48 (2H, 2d, 2'- and 3'-OH), 5.92 (1H, d, H-1'), 7.06-7.24 (4H, m, Ar--H), 8.20 and 8.40 (3H, s and br s, H-2, H-8 and N--H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.[CH2:30]=O.Cl.[CH3:33][NH:34][CH3:35].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:18][CH2:33][N:34]([CH3:30])[CH3:35])=[O:17])=[N:14][CH:15]=1
Reactant: CNC
Reactant: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)NCN(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (150 mg, 0.33 mmol) obtained in Example 15 in N,N-dimethylformamide (3 ml), a formaldehyde solution (37%, 54 μl) and dimethylamine hydrochloride (136 mg, 1.67 mmol) were added at 0° C., and the mixture was stirred for 2 hours at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and was dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography. The fraction obtained from an elution with dichloromethane:methanol=10:1 was concentrated under reduced pressure, and the resulting residue was washed with diethyl ether and dichloromethane and dried, to obtain the title compound (99 mg, 0.21 mmol, 63%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]3=[O:28])[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC(O)C>C(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]3=[O:28])[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH:13][C:14]2[N:19]=[C:18]([N:20]3[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]3=[O:28])[CH:17]=[CH:16][N:15]=2)[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(C)Nc2nccc(N3C(=O)OC[C@@H]3C(C)C)n2)cc1OC
Agent: O=C=O
Solvent: CC(C)O
Product: COc1ccc([C@@H](C)Nc2nccc(N3C(=O)OC[C@@H]3C(C)C)n2)cc1OC
Product: COc1ccc([C@H](C)Nc2nccc(N3C(=O)OC[C@@H]3C(C)C)n2)cc1OC

Procedure:
A mixture of (4S)-3-(2-((1-(3,4-dimethoxyphenyl)ethyl)amino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (example 118) was resolved on a column (AS-H 4.6×100 mm) using 30% iPrOH in CO2 to give (S)-3-(2-((R)-1-(3,4-dimethoxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one and (S)-3-(2-((S)-1-(3,4-dimethoxyphenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:14][C@@H:13]([C:15](=[O:17])[NH2:16])[N:12]1CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.O>CO.[Pd]>[C:15]([C@H:13]1[NH:12][C@@H:11]([C:9]([OH:10])=[O:8])[CH2:14]1)(=[O:17])[NH2:16]
Reactant: NC(=O)[C@@H]1C[C@H](C(=O)OCc2ccccc2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)[C@@H]1C[C@H](C(=O)O)N1
Yield: 96.2 %

Procedure:
53 mg (163 μmol) of cis-1-benzyl-4-carbamoyl-azetidine-2-carboxylic acid benzyl ester (II) in 10 ml of methanol are hydrogenated in a Parr shaker over 18 mg of 10% Pd/C under a hydrogen pressure of 3.3 atm for 3 hours. 10 ml of water is added, the mixture filtered through a fluted filter, and the catalyst washed with several portions of methanol. Evaporation and drying in vacuo (0.1 torr, 4 hours) affords 22.6 mg (96%) of a colorless glass. 1H NMR (D2O): δ5.00 (t, 1H, J=9), 4.75 (t, 1H, J=9), 3.14 (dt, 1H, J=10 (t), 12 (d)), 2.52 (dt, 1H, J=8(t), 12 (d)). IR (nujol): 3399, 3141, 3019, 2537, 2409, 1688, 1615, 1563, 1391, 1294, 1217, 1165, 1115, 1048, 968, 887, 810, 762, 696, 637 cm-1. Mass Spectra: EI: m/z 142(M-2H, 40%), 100 (100), 91 (14), 82 (27), 68 (28), 54 (50), 44 (95); CI (isobutane): m/z 145 (M+H, 100%), 126 (7), 100 (24), 99 (15), 84 (15), 72 (22).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].[CH2:15]=[O:16].[C:17]([O-:20])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:12])([CH3:13])[C:6]([CH2:17][OH:20])([CH2:15][OH:16])[C:5]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: C=O
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)Oc2ccc(Br)cc2C(=O)C1(CO)CO
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a mixture of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.00 g, 3.92 mmol) and dioxane (10 mL) were added formaldehyde (37 wt. % in water, 2.95 mL, 39.2 mmol) and Na2CO3 (831 mg, 7.84 mmol) at room temperature. After stirring overnight at the same temperature, the reaction mixture was filtered. The filtrate was diluted with CHCl3, washed with 1M aqueous HCl and water, dried over MgSO4 and filtered. The filtrate was concentrated at reduced pressure, and the residue was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 0 to 50%) to afford 6-bromo-3,3-bis(hydroxymethyl)-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (1.07 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:10]1[CH2:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:7][C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: N=C(N)NN
Reactant: Cc1ccccc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 97.5 %

Procedure:
A mixture of 4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.30 g), aminoguanidine hydrochloride (0.14 g), concentrated hydrochloric acid (0.018 ml), water (0.018 ml) and ethanol (30 ml) was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate and concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give 5-guanidinoimino-4-methyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 57) (0.4 g) as colorless crystals.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:19].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9](=[O:17])[C:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(C(O)Cc2ccncc2)c1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CSc1cccc(C(=O)C(=O)c2ccncc2)c1
Reaction time: 12 h
Yield: 5.5 %

Procedure:
To a solution of 1-(3-methylthiophenyl)-2-(4-pyridyl)ethanol (2.5 g, 10.2 mmol) in CH2Cl2 (150 mL) was added a mixture of celite (4.4 g) and pyridinium dichromate (4.4 g, 20.4 mmol). After stirring for 12 h, the mixture was filtered through celite. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with a solvent gradient of 40-50% EtOAc/Hex to provide the title compound (144 mg, 5.5%): 1H NMR (CDCl3): d 8.88 (br d, 2H); 7.85 (s, 1H); 7.78 (d, 2H); 7.67(d, 1H); 7.56 (d, 1H); 7.44 (t, 1H); 2.55 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1.[Br:26][C:27]1[N:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN1C(=O)CCC1>[Br:26][C:27]1[N:32]=[C:31]([C:33]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=[C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[CH:9]=2)=[O:34])[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2N)nc(C(F)(F)F)n1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccncc2NC(=O)c2cccc(Br)n2)nc(C(F)(F)F)n1
Yield: 95 %

Procedure:
Method 27 was followed using tert-butyl 6-(3-aminopyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-ylcarbamate (1.0 equiv.), 6-bromopicolinic acid (1.0 equiv.), EDC (1.0 equiv.), and HOAt (1.0 equiv.) in NMP yielding tert-butyl 6-(3-(6-bromopicolinamido)pyridin-4-yl)-2-(trifluoromethyl)pyrimidin-4-ylcarbamate>95% yield. LCMS (m/z): 539/541 (MH+); LC Rt=3.97 min.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].C1([NH2:36])CCCCC1.C1(C)C=CC=CC=1>C(OC(=O)C)C>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH:13]1([C:8]([NH2:36])=[O:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:12]1
Reactant: NC1CCCCC1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NC(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 5 g (0.012 mol) of lovastatin, 6 ml (0.052 mol) of cyclohexylamine and 50 ml of toluene was refluxed for 6 hours. The reaction mixture was cooled to room temperature and 20 ml of ethylacetate was added. The mixture was washed with 2N HCl (2×30 ml) and water (2×20 ml). The organic layer was dried with sodium sulfate, filtered and evaporated to a volume of 15 ml. 50 ml of hexane was added and the precipitate was filtered to give 5.5 g of lovastatin cyclohexanamide as a white powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1>>[F:11][C:4]1[CH:3]=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: OB(O)c1cccnc1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: O=C(O)c1ccc(-c2cccnc2)cc1F

Procedure:
The title compound is prepared as described in EXAMPLE 31, Part I, but with 4-bromo-2-fluorobenzoic acid and 3-pyridinylboronic acid as starting materials. 1H NMR (DMSO) δ 8.97 (d, 1H), 8.66-8.58 (m, 1H), 8.22-8.12 (m, 1H), 8.00-7.91 (m, 1H), 7.81-7.62 (m, 2H), 7.55-7.45 (m, 1H). ESI MS (M+1)+: 218.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[C:5]([I:10])=[CH:4][N:3]=1.[Br:11]CC1C(Cl)=NC(Cl)=C(F)C=1>>[Br:11][CH2:8][C:6]1[C:5]([I:10])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Reactant: OCc1cc(Cl)ncc1I
Product: Clc1cc(CBr)c(I)cn1

Procedure:
Compound 77A was prepared from (2-Chloro-5-iodo-pyridin-4-yl)-methanol (0.2 g, 1.38 mmol) using a procedure similar to the synthesis of 1B.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][CH:9]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.C(OC([N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1)=O)(C)(C)C>ClCCl>[NH:50]1[CH2:55][CH2:54][CH:53]([NH:56][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:4]3[CH:3]=[C:2]([Cl:1])[C:7]([CH2:8][CH:9]4[CH2:13][CH2:12][N:11]([CH:14]5[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]5)[C:10]4=[O:20])=[C:6]([Cl:21])[CH:5]=3)=[CH:27][CH:26]=2)=[O:29])[CH2:52][CH2:51]1
Reactant: O=C(O)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1CCNCC1)c1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Dissolve racemic 3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carboxylic acid (0.200 g, 0.448 mmol) in dichloromethane (5 mL) and add 1,1′-carbonyl-diimidazole (0.125 g, 0.760 mmol). Stir under argon atmosphere at room temperature and check reaction progress via TLC. Add 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.180 g, 0.90 mmol) and continue to stir until the starting material has been fully consumed. Dilute the reaction with dichloromethane (50 mL) and wash with 1.0 N sodium hydroxide (30 mL) then brine (30 mL). Collect the organic phase, dry over anhydrous magnesium sulfate and concentrate under reduced pressure. Purify via flash chromatography by eluding with gradient (0-100%) dichloromethane to 15% ammonia methanol/85% dichloromethane. After concentrating, dissolve the 4-{[3′,5′-dichloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-4-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester in dioxane (20 mL), add 4N hydrochloric acid -dioxane (10 mL) and stir ½ hour to obtain an oily residue in reaction vessel. Concentrate the mixture under vacuum then dilute in dichloromethane (100 mL). Quench with saturated aqueous sodium bicarbonate solution (50 mL), dry the organic phase over magnesium sulfate and concentrate to obtain 0.195 g (82%) of a yellow foam: MS (m/z): 530 (M+2).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:20])=[O:19])[O:15][C:14]3=[O:21])=[CH:9][C:8]=2[F:22])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([C:18]([NH2:20])=[O:19])[O:15][C:14]3=[O:21])=[CH:9][C:8]=2[F:22])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: NC(=O)[C@H]1CN(c2ccc(C3=CCOCC3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: NC(=O)[C@H]1CN(c2ccc(C3CCOCC3)c(F)c2)C(=O)O1

Procedure:
A mixture of (5R)-(−)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide (EXAMPLE 443, Step 2, 200 mg, 0.653 mmol) and 10% palladium-on-carbon (139 mg, 0.131 mmol) in methanol (26 mL) was shaken under a 40 psi hydrogen atmosphere on a Parr apparatus for 5 hours. The catalyst was then removed by filtration through a pad of Celite, and the filtrate was concentrated under reduced pressure and chromatographed on a Flash 40S 40 g silica gel (32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf=0.37 by TLC (methanol/chloroform, 2×5/95) gives the title compound, mp 153-156° C.; MS (ESI−) for C15H17N2O4F m/z 307 (M−H)−; [α]25D=−21 (c 0.87, DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH3:17])=[CH:12]2)=[O:5].[Br:23]N1C(=O)CCC1=O.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>ClCCl.C(OCC)(=O)C>[Br:23][C:10]1[CH:9]=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:2]=2[Cl:1])=[C:16]2[C:11]=1[CH:12]=[C:13]([CH3:17])[CH:14]=[N:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)ccc(Br)c2c1
Yield: 17.5 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-3-methylquinoline (250 mg), N-bromosuccinimide (175 mg) and 2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (23.3 mg) in dichloromethane was refluxed for 2 hours. After cooling, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (dichloromethane) to give 5-bromo-8-(2,6-dichlorobenzoylamino)-3-methylquinoline (54.2 mg).
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=C(F)C=1)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32]CO)[N:31]=2)=[CH:23][CH:22]=1.COC1C=CC(C(N)=S)=CC=1.[Cl:46]CC(CCl)=O>>[Cl:46][CH2:32][C:30]1[N:31]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[S:28][CH:29]=1
Reactant: COc1ccc(-c2nc(CCO)cs2)cc1
Reactant: O=C(CCl)CCl
Agent: CCOC(=O)C(Cc1ccc(O)c(F)c1)OCC
Agent: COc1ccc(C(N)=S)cc1
Product: COc1ccc(-c2nc(CCl)cs2)cc1

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (example 7 a]) was reacted with 2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-methoxy-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a] to yield 4-chloromethyl-2-(4-methoxy-phenyl)-thiazole, followed by side chain elongation in analogy to the sequence described in examples 13 a] to 13 d]) in tetrahydrofuran in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-(3-fluoro-4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([OH:54])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:60](=O)(O)[O-].[Na+].O>CO>[CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=4[F:51])[CH:34]=3)[O:32][C@@:10]1([C:52]([O:54][CH3:60])=[O:53])[CH2:11][O:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(=O)OC)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 40 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-carboxylic acid 24a (507 mg, 0.67 mmol) in methanol (10 mL) was added concentrated sulphuric acid (0.04 mL, 0.74 mmol) at room temperature. The mixture was warmed up to 40° C. and stirred for 7 hours. The reaction mixture was cooled to room temperature and adjusted with saturated aqueous sodium bicarbonate to pH 7. To the mixture was added 10 mL of water and the resulting mixture was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=15/1 to give the title compound 24b as colorless oil (320 mg, 62%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.39 (m, 10H), 7.20 (m, 6H), 6.89 (d, 2H), 6.63 (t, 1H), 6.51 (t, 1H), 4.83 (m, 3H), 4.63 (d, 1H), 4.53 (d, 1H), 4.30 (d, 1H), 4.20 (d, 2H), 4.08-3.97 (m, 5H), 3.90 (d, 1H), 3.75 (m, 1H), 3.71 (s, 3H), 1.44 (t, 3H).