Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][OH:20])=[O:12])=[C:4]([F:21])[CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH2:19][O:20][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:12])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(NC(=O)N2CCCCC2CO)c(F)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1cc(NC(=O)N2CCCCC2COC(=O)C(C)(C)C)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
15.9 g (0.05 mol) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-hydroxymethylpiperidine (Example 1) and 4.7 g (0.06 mol) of pyridine are dissolved in 200 ml of toluene, and 6.0 g (0.05mol) of pivaloyl chloride are added dropwise at 20° C. The mixture is stirred for 3 hours at 50° C. and washed with twice 100 ml of water, and the toluene phase is dried over sodium sulfate. After the solvent as been removed, 18.4 g (92% of theory) of 1-[N-(4-chloro-2-fluoro-5-methoxyphenyl)-carbamoyl]-2-pivaloyloxymethylpiperidine are obtained in the form of a colorless viscous oil.
Reaction SMILES: C(OC(N([C@@H](C1C=CC=CC=1)C)C(=O)[CH:9]([CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=O)(C)C.[CH3:28][O-:29].[Na+].C1C[O:34][CH2:33]C1>CO>[CH2:13]([CH:12]([CH2:11][CH2:10][CH2:9][CH2:16][CH2:17][CH3:18])[C:28]([O:34][CH3:33])=[O:29])[CH:14]=[CH2:15]
Reactant: C1CCOC1
Reactant: C[O-]
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)OC(C)C)[C@H](C)c1ccccc1
Agent: [Na+]
Solvent: CO
Product: C=CCC(CCCCCC)C(=O)OC
Reaction time: 7 h

Procedure:
A solution of 0.374 g (1.0 mmol) of N-isopropyloxycarbonyl-N-(2-allyloctanoyl)-1-(R)-phenylethylamine ((1R,2S):(1R,2R)=77.6:22.4) in 5 ml of THF was cooled to 0° C. A solution of 11 mg (0.2 mmol) of NaOMe in methanol (0.04 g) was added, and the mixture was stirred for 7 hours. The reaction was terminated by addition of 1 ml of 1 N hydrochloric acid, and the product was extracted with ethyl acetate (30 ml×2). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was quantitated by GC. Thus was obtained 0.163 g (82%, 55.0% ee) of the title compound.
Reaction SMILES: [Na].[I-].[CH3:3][N+:4]1[CH:9]=[CH:8][C:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:6]=2[CH:5]=1.O>C(O)C>[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]2[C:10]3[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=3[CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH:6]2[CH2:5]1
Reactant: C[n+]1ccc2c(c1)-c1ccccc1Cc1ccccc1-2
Agent: [I-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN1CCC2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g Sodium is added with stirring and under a nitrogen atmosphere to a suspension of 0.5 g 2-methyl-9H-dibenzo[1,2;5,6]cyclohepta[3,4-c]pyridinium iodide (formula IV, melting point>300° C.) in 50 ml ethanol, after which the mixture is refluxed for 1 hour. The reaction mixture is then poured out into H2O and extracted with methylene chloride. The organic phase is washed with H2O, dried over Na2SO4 and evaporated to dryness.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][C:27]1[N:28]=[C:29]([NH2:42])[S:30][C:31]=1[S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[CH3:26][C:27]1[N:28]=[C:29]([NH:42][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[S:30][C:31]=1[S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]
Reactant: Cc1nc(N)sc1S(=O)(=O)N1CCN(C)CC1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1nc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)N1CCN(C)CC1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-methyl-5-(4-methyl-piperazine-1-sulfonyl)-thiazol-2-ylamine (example B.19) according to general procedure II.
Reaction SMILES: [Br-].C([N+:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[BH4-].[Na+].[Cl:22]C(OCC)=O>C(O)C.O>[ClH:22].[C:15]([OH:17])(=[O:16])[C:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cc[n+](Cc2ccccc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cl
Product: O=C(O)C1=CCNCC1
Temperature: 10 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
1-Benzyl-4-ethoxycarbonylpyridinium bromide (580 g, 1.80 mol) is suspended in a mixture of ethanol (900 ml) and water (900 ml), and thereto is added sodium borohydride (74.9 g, 1.98 mol) in portions while the temperature of the reaction mixture is kept at a temperature below 10° C. The reaction mixture is stirred at 10° C. for three hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in chloroform. The mixture is washed with water, dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is dissolved in chloroform (500 ml), and thereto is added dropwise ethyl chloroformate (215 g, 1.98 mol) under reflux over a period of one hour. The mixture is further refluxed for 30 minutes, and concentrated under reduced pressure. To the residue are added conc. hydrochloric acid (504 g) and water (150 g), and the mixture is refluxed for 10 hours. The reaction mixture is cooled to room temperature, and concentrated under reduced pressure. To the residue is added isopropyl alcohol (500 ml), and the mixture is stirred. The precipitated crystals are collected by filtration with suction, and washed with a small amount of ether, and dried with air to give 1,2,5,6-tetrahydroisonicotinic acid hydrochloride (151.7 g, 52%), as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][C:20]4[N:16]([N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[CH:19]=4)[C:15]=3[CH:32]=2)[CH2:8]1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[CH:19]=[C:20]3[N:16]([C:15]4[CH:32]=[C:11]([CH:9]5[CH2:10][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8]5)[CH:12]=[CH:13][C:14]=4[O:23][CH2:22][CH2:21]3)[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(C(C)(C)CO)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (200 mg, 0.55 mmol), 2-bromo-2-methyl propionate (71 μL, 0.55 mmol), triethylamine (75 μL, 0.55 mmol) in DMF was heated at 55° C. for 30 h before concentrating in vacuo. The residue was partitioned between 10% MeOH in DCM and water, the aqueous extracted with 10% MeOH in DCM and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 23%). To a solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 0.12 mmol) in THF (1.5 mL) at −78° C. was added DIBAL (1.5 M solution in toluene, 0.24 mL, 0.36 mmol) and the mixture allowed to warm to RT over 18 h. The mixture was cooled to 0° C., further DIBAL (0.12 mL, 0.18 mmol) added dropwise and stirring continued for 45 min. The reaction was quenched by the addition of MeOH (0.5 mL) followed by Rochelle's salt saturated aqueous solution (0.5 mL), then diluted with ethyl acetate and filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH (+2M NH3) in DCM) to give 170 as a white solid, as illustrated in FIG. 13 (27 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.85 (d, J=2.18 Hz, 1H); 7.23 (d, J=2.23 Hz, 1H); 7.17 (d, J=8.29 Hz, 1H); 6.87 (s, 1H); 5.74-5.66 (m, 1H); 4.55 (t, J=6.02 Hz, 2H); 3.71 (s, 3H); 3.43 (s, 2H); 3.28 (s, 2H); 3.16 (t, J=6.03 Hz, 2H); 1.59 (d, J=6.62 Hz, 6H); 1.04 (s, 6H). 1 Exchangeable proton not observed. LCMS: RT=6.43 min, M+H+=423
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1O)(=[O:3])[CH3:2].O.[CH2:17]([NH2:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[CH2:30]([OH:32])[CH3:31]>ClCCl>[CH2:17]([N:29]([CH:6]1[O:8][C@H:9]([CH2:14][OH:15])[C@@H:10]([OH:13])[C@H:11]([OH:12])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])[C:30](=[O:32])[CH2:31][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCN
Reactant: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CCO
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Temperature: 25 °C

Procedure:
26 g of N-acetylglucosamine were dissolved in 100 ml of ethanol and 60 ml of water and heated to 60°. 37 g of dodecylamine were added and stirred until a clear solution was achieved. The glycosylamine crystallised out after cooling down to room temperature. The mass of crystals was filtered off with suction, washed with ethanol and then with ether and dried in vacuo. 3 g of the solid material were suspended in 50 ml of tetrahydrofuran, 3.3 g of sodium carbonate were added and 1.9 g of tetradecanoyl chloride in 10 ml of tetrahydrofuran were added. After completion of reaction, the mixture was diluted with 30 ml of dichloromethane, filtered and the filtrate was evaporated in vacuo. The syrup obtained was purified by chromatography (mobile phase dichloromethane/methanol 20/1, (v/v)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[C:17]([C:18]([F:21])([F:20])[F:19])=[C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:15][N:14]=3)=[C:8]1[CH2:7][CH2:6]2.C(O)(=O)C.[NH:35]1[CH2:38][CH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1.C(N(CC)CC)C>CN(C=O)C>[C:22]1([C:16]2[O:15][N:14]=[C:13]([C:12]3[O:11][N:10]=[C:9]4[C:28]5[C:5]([CH2:6][CH2:7][C:8]=34)=[CH:4][C:3]([CH2:2][N:35]3[CH2:36][CH:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]3)=[CH:30][CH:29]=5)[C:17]=2[C:18]([F:20])([F:21])[F:19])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(CBr)ccc2-3)noc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a cloudy solution of 7-(bromomethyl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6C, 550 mg, 1.157 mmol) and tert-butyl azetidine-3-carboxylate acetic acid (377 mg, 1.736 mmol) in anhydrous DMF (12 mL) was added triethylamine (0.645 mL, 4.63 mmol) dropwise at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hr before being concentrated. The solid residue was partitioned between dichloromethane (2 mL) and saturated aqueous sodium bicarbonate solution (6 mL). The aqueous layer was extracted with dichloromethane (2×2 mL). The combined dichloromethane solutions were dried over sodium sulfate, concentrated and purified by silica gel chromatography (20 to 75% ethyl acetate in heptane) to afford tert-butyl 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylate (520 mg, 0.943 mmol, 81% yield) as a solid. To the solid was added TFA (3 mL) and the mixture stirred at room temperature for 70 min before being concentrated. Dichloromethane (15 mL) was added and the mixture concentrated again. The residue was mixed with water (4 ml) and neutralized to pH=5 with an aqueous sodium acetate solution. The resulting solid was filtered and washed with water (3×1 mL). To the solid was added methanol (1 mL) and water (0.5 mL), the contents were sonicated, and filtered. To the solid was added acetonitrile (0.5 mL) and water (6 mL). Lyophilization gave 1-((3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)methyl)azetidine-3-carboxylic acid (420 mg, 0.805 mmol, 69.6% yield) as a white solid. The compound had an HPLC retention time=3.25 min. (condition C). LC/MS M+1=496.2. 1H NMR (400 MHz, MeOD+CDCl3) δ ppm 8.06 (1H, d, J=7.9 Hz), 7.77 (2H, d, J=7.3 Hz), 7.59-7.71 (3H, m), 7.51 (1H, s), 7.48 (1H, d, J=7.7 Hz), 4.42 (2H, s), 4.25-4.34 (4H, m), 3.55-3.65 (1H, m), 3.14 (4H, s).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a 500 mL 3-necked flask equipped with reflux condenser, addition funnel, nitrogen inlet and magnetic stirring was added 50.0 g (0.277 mol, 1.0 eq.) 4-iodophenol (Aldrich), 37.69 g (0.2727 mol, 1.2 eq.) potassium carbonate (Fischer) and 250 mL dimethylformamide (DMF) and the mixture was heated to 65° C. for 20 minutes. To the addition funnel was added 48.61 g (0.284 mol., 1.25 eq) benzylbromide (Aldrich) and 50 mL DMF. The heat was turned off and the contents of the addition funnel were added dropwise over 15 minutes during which time an exotherm to 75° C. was produced with salt formation. Heating was resumed at 45° C. for an additional 20 hours after which liquid chromatography (LC) indicated complete conversion. The mixture was poured onto ice and extracted with Et2O, dried over sodium sulfate (Na2SO4), reduced in vacuo and recrystallized from ethanol giving 44.2 g of 1 as tan crystals (m.p.=55°-56° C.) in 63 percent isolated yield (99 percent by LC). It had the following spectral properties. 1H NMR (250 MHz, CDCl3): δ4.82 (s,2H), 6.54 (d), 7.12-7.2 (m), 7.34 (d). 13C NMR (63 MHz, CDCl3 : δ70.1, 117.3, 127.4, 128.1, 128.6, 136.5, 138.2, 158.7. HRMS m/z (EI) calcd (found) for C13H11 OI=309.9855 (309.9851).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([NH:8][C:9]([O:11]CC2C=CC=CC=2)=O)[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3]1.C(N(CC)CC)C.Br[CH2:32][C:33]1[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][CH:40]=[CH:39][C:34]=1C(OC)=O>C(O)(=O)C.CN(C)C=O.[Pd]>[N+:43]([C:42]1[CH:41]=[CH:40][CH:39]=[C:34]2[C:33]=1[CH2:32][N:8]([CH:7]1[CH2:6][CH:5]([O:19][C:20](=[O:22])[CH3:21])[C:4](=[O:23])[NH:3][C:2]1=[O:1])[C:9]2=[O:11])([O-:45])=[O:44]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)C(=O)NC1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)OC1CC(N2Cc3c(cccc3[N+](=O)[O-])C2=O)C(=O)NC1=O

Procedure:
A solution of 2,6-dioxo-3-benzyloxycarbonylamino-5-acetoxypiperidine (9 g, 28.2 mmol) and Pd/C (10%, 0.9 g) in acetic acid (90 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with acetic acid and the solvent is then removed in vacuo. The residue, triethylamine (2.9 g, 28 mmol), and methyl 2-bromomethyl-3-nitrobenzoate (7.7 g, 28.2 mmol) in dimethylformamide (100 mL) is heated at 80° C. for 18 hours. The solvent is removed in vacuo to give 3-(4-nitro-1-oxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine which can be further purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:14][CH:13]=1)[C:8]([OH:10])=[O:9])=[O:5].[CH3:36][CH2:37][CH2:38][CH2:39][N:40]([C:45]1[C:50]2[CH:51]=[CH:52][CH:53]=[C:54]([S:55](Cl)(=[O:57])=[O:56])[C:49]=2[CH:48]=[CH:47][CH:46]=1)[CH2:41][CH2:42][CH2:43][CH3:44].[CH2:59](Cl)Cl>>[CH3:59][O:9][C:8](=[O:10])[C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:31]=[C:32]([Cl:35])[CH:33]=[CH:34][C:2]=1[NH:1][S:55]([C:54]1[C:49]2[C:50](=[C:45]([N:40]([CH2:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38][CH2:37][CH3:36])[CH:46]=[CH:47][CH:48]=2)[CH:51]=[CH:52][CH:53]=1)(=[O:57])=[O:56])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:16][CH:17]=1
Reactant: ClCCl
Reactant: CCCCN(CCCC)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: Nc1ccc(Cl)cc1C(=O)NC(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)C(=O)O
Product: CCCCN(CCCC)c1cccc2c(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)N[C@@H](Cc3ccc(-c4ccccc4Oc4ccccc4)cc3)C(=O)OC)cccc12
Yield: 74 %

Procedure:
A solution of 2-(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid (0.05 g, 0.1 mmol) [prepared by reacting (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)propionic acid methyl ester hydrochloride salt and 2-amino-5-chlorobenzoic acid by general procedure A] in CH2Cl2 was treated with (0.035 g, 0.1 mmol) of bansyl chloride according to the general procedure F. Product was purified by flash column chromatography on silicagel using ethyl acetate hexanes to give product as pale yellow solid (0.06 g, 74.0% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(C)C=CC=CC=1>O>[Cl:3][CH2:22][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][CH:24]=1)[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Thionyl chloride (4.45 ml) was added dropwise to a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.0 g) and toluene (200 ml) at 0° C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (13.4 g, yield 84%) as pale-yellow crystals. m.p. 79-80° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)=[CH:23][N:22]=3)[CH2:17]2)=[O:15])[CH:8]=1.[CH3:34][O:35][CH2:36][CH2:37]Br>CN(C=O)C>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:37][CH2:36][O:35][CH3:34])[CH:28]=4)=[CH:23][N:22]=3)[CH2:17]2)=[O:15])[CH:8]=1
Reactant: O=C(Nc1cccnc1)N1CC(Oc2ccc(-c3cccc(O)c3)cn2)C1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(-c2ccc(OC3CN(C(=O)Nc4cccnc4)C3)nc2)c1
Temperature: 100 °C
Yield: 29 %

Procedure:
Potassium carbonate (23 mg, 165 μmol) was added to a solution of 3-[5-(3-hydroxy-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid pyridin-3-ylamide (20 mg 55 μmol), in DMF (0.5 mL). 2-Bromoethyl methyl ether (6 μL, 66 μmol) was added and the reaction mixture was heated to 100° C. in microwave synthesiser for 1 hr. The reaction mixture was allowed to cool and solvent removed in vacuo. The crude product was purified by preparative HPLC to afford the title product as a colourless solid (6.7 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:14][CH:13]=1
Reactant: NCC(c1ccc(Cl)cc1)N1CCOCC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC(c1ccc(Cl)cc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and 2-(4-chloro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Reactant: C[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)N[C@@H](C)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=509) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale yellow foam (0.61 g, 67%).