Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:46])[NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]4[S:35][CH:34]=[C:33]([C:36]5[NH:37][C:38]([C@@H:41]6[CH2:45][CH2:44][CH2:43][NH:42]6)=[N:39][CH:40]=5)[C:30]=4[S:31][CH:32]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8].[C:47]([O:51][C:52]([NH:54][C@H:55]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:56](N1CCC[C@H]1C(O)=O)=[O:57])=[O:53])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C)C=O>[CH3:2][O:3][C:4](=[O:46])[NH:5][C@H:6]([C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]4[S:35][CH:34]=[C:33]([C:36]5[NH:37][C:38]([C@@H:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:56](=[O:57])[C@H:55]([NH:54][C:52]([O:51][CH3:47])=[O:53])[C:66]6[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=6)=[N:39][CH:40]=5)[C:30]=4[S:31][CH:32]=3)=[CH:24][CH:23]=2)[N:21]=1)=[O:11])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6)[nH]5)csc34)cc2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3csc4c(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)csc34)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 25 %

Procedure:
To a mixture of compound 71 (0.078 mmol), compound 33 (0.085 mmol), and HATU (0.085 mmol) in dimethylformamide (1 mL) was added Et3N (0.465 mmol) dropwise. The reaction mixture was stirred at room temperature during 12 hrs. The solvent was removed under reduced pressure and the residue was dissolved in methanol. This mixture was eluted through a SCX-2 column. The filtrate was concentrated and the residue was purified by semi-preparative HPLC to give compound A200 as a white solid in 25% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 0.85 (d, J=6.46 Hz, 3H), 0.91 (d, J=6.64 Hz, 3H), 1.84-2.20 (m, 8H), 3.11-3.22 (m, 1H), 3.35-3.38 (m, 1H), 3.51-3.54 (m, 6H), 3.77-3.92 (m, 2H), 4.04-4.09 (m, 1H), 5.06-5.11 (m, 2H), 5.48-5.52 (m, 1H), 6.88-8.40 (m, 13H), 11.80-11.87 (m, 1H); MS (ESI, EI+) m/z=835.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][NH:11]1.Cl[CH2:16][CH:17]1[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH:17]1([CH2:16][N:9]([C:10]2[NH:14][CH2:13][CH2:12][N:11]=2)[C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:19][CH2:18]1
Reactant: Clc1cccc(Cl)c1N=C1NCCN1
Reactant: ClCC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1N(CC1CC1)C1=NCCN1
Yield: 10.6 %

Procedure:
A mixture consisting of 6.9 gm (0.03 mol) of 2-(2,6-dichlorophenyl-imino)-imidazolidine, 2.9 gm (110% of stoichiometrically required amount) or chloromethyl-cyclopropane, 4 gm of sodium carbonate and 50 ml of absolute toluene was refluxed for 32 hours, while stirring. Thereafter, the reaction solution was evaporated to dryness in vacuo, and the residue was dissolved in about 1N hydrochloric acid. The resulting acidic solution was extracted several times with ether, and the ethereal extracts were discarded. The acidic aqueous phase was then fractionally extrated with ether at stepwisely increasing pH-values (alkalization with dilute sodium hydroxide), and the thin-layer chromatographically pure fractions were combined, dried over magnesium sulfate and evaporated in vacuo, yielding as the residue 0.9 gm (10.6% of theory) of the compound of the formula ##STR7## which had a melting point of 126°-129° C.
Reaction SMILES: O=[C:2]1[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C@H:3]1[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1C=CC=CC=1>[C:17]1([CH2:16][CH2:15][CH2:14][CH:3]2[C:2](=[S:32])[NH:6][C@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](CCCc2ccccc2)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)[C@@H]1CC(CCCc2ccccc2)C(=S)N1
Yield: 179.8 %

Procedure:
A mixture of pyroglutamate 8c (245.4 mg, 0.809 mmol) and Lawesson's reagent (164 mg, 0.404 mmol) in 6 mL benzene was stirred at reflux for 17 h, then concentrated. The crude product was purified by flash chromatography (0.5 to 1 to 1.5 to 2% MeOH/CHCl3) to afford 232 mg (90%) of the thiolactam 8d as a 2:1 mixture of diastereomers.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[N:10]=[CH:9]2)C=CC=CC=1.[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][C:33]=1[F:40])#[N:31]>C(#N)C>[C:30]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:10]2[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:8]=[CH:9]2)=[CH:34][C:33]=1[F:40])#[N:31]
Reactant: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CC#N
Product: COC(=O)Cc1cncn1Cc1ccc(C#N)c(F)c1
Temperature: 50 °C
Yield: 164.7 %

Procedure:
A solution of methyl 1-(triphenylmethyl)imidazol-4-ylacetate from Step B (0.536 g, 1.40 mmol) and 4-cyano-3-fluoro-benzylbromide from Example 1, Step D (0.300 g, 1.40 mmol) in dry acetonitrile (3 mL) was heated at 50° C. under argon for 2 hours, then the precipitate was collected by filtration. The filtrate was concentrated to a volume of 1 mL and then heated at 50° C. for a further 2 hours. The precipitate formed was collected and combined with the first crop to give a white solid (0.63 g). This solid was dissolved in MeOH (30 mL) and heated to reflux for 2 hours. The MeOH was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (20 mL) and CHCl3 (30 mL). The aqueous layer was extracted further with CHCl3 (2×15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with 3% MeOH/0.3% NH4OH in CHCl3 to give the titled product as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]([C:10]1[N:14](CC2C=CC=CC=2)[N:13]=[N:12][N:11]=1)=[O:9])(=O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([C:4]1[C:5]([OH:25])=[C:6]([CH:22]=[CH:23][CH:24]=1)[NH:7][C:8]([C:10]1[NH:14][N:13]=[N:12][N:11]=1)=[O:9])[CH3:2]
Reactant: CC(=O)c1cccc(NC(=O)c2nnnn2Cc2ccccc2)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCc1cccc(NC(=O)c2nnn[nH]2)c1O
Reaction time: 6 h
Yield: 16.7 %

Procedure:
A solution of 3'-acetyl-1-benzyl-2'-hydroxy-1H-tetrazole-5-carboxanilide (2.6 g) in glacial acetic acid (100 ml) was hydrogenated at 52° C. and 4.1 kg/cm2 for 6 hours, using a catalyst of palladium on charcoal (5% w/w). The mixture was filtered and the filtrate was evaporated in vacuo to give a solid residue, which was recrystallised by dissolving in hot dimethylformamide (7 ml) and slowly adding a large volume of water (100 ml). The colourless solid which crystallised out was collected and discarded as an unwanted by-product. The mother liquor was evaporated under diminished pressure, and the resulting residue was recrystallised from a small volume of aqueous dimethylformamide to give 3'-ethyl-2'-hydroxytetrazole-5-carboxanilide (0.3 g) in the form of pale cream crystals, m.p. 185°-187° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH3:30][C:31]1[C:35]([NH:36][C:37](=O)[OH:38])=[C:34]([CH3:40])[O:33][N:32]=1>>[CH3:30][C:31]1[C:35]([NH:36][C:37](=[O:38])[NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[C:34]([CH3:40])[O:33][N:32]=1
Reactant: Cc1noc(C)c1NC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1noc(C)c1NC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 3,5-dimethylisoxazol-4-ylcarbamic acid hydrochloride, gave Compound 172, (S)-2-(3-(3,5-dimethylisoxazol-4-yl)ureido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 11.99 (br s, 1H), 9.62 (br s, 1H), 8.40-8.38 (d, 1H), 7.55 (s, 1H), 7.36-7.19 (m, 8H), 7.07-7.02 (m, 2H), 6.94-6.76 (m, 3H), 4.74-4.69 (m, 1H), 4.53 (s, 2H), 3.77-3.64 (m, 2H), 3.53-3.42 (m, 2H), 2.06 (s, 3H). MS (EI) for C28H27FN4O4. found 503.0 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[C:16]([S:17]([NH:20][C:21]2[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[C:16]([S:17]([N:20]([C:21]2[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=2)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1Cl
Reaction time: 0.67 h

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.315 ml) was added dropwise to a stirred solution of 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) and N,N-diisopropylethylamine (0.347 ml) in dry DMF (7 ml) at -15° C. Stirring was continued for 40 minutes at this temperature after the addition was complete. Ethyl acetate (40 ml) was added and the mixture was washed with water (3×15 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.462 g) as an oil; 1H NMR (CDCl3): 0.0 (s, 9 H), 0.85 (t, 2 H), 2.5 (s, 3 H), 3.75 (t, 2 H), 3.8 (s, 3 H), 5.3 (s, 2 H), 7.3 (dd, 1 H), 7.8 (s, 1 H), 8.4 (dd, 1 H), 8.5 (dd, 1 H); mass spectrum (+ve ESP): 403 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][C@@H:10]2[CH3:16])[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:10]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][N:9]1[C:6]1[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=1
Reactant: NN
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)C[C@@H]2C)n1
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(NN)c(F)c(N2CCN(C)C[C@@H]2C)n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 43 %

Procedure:
4-Chloro-6-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.277 g, 1.07 mmol), hydrazine monohydrate (0.5 mL) and DMSO (2.0 mL) were stirred at room temperature overnight. Then the reaction was heated to 50° C. and stirred for 7 hours. Purified by RP-HPLC to provide 4-[(2S)-2,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as an orange solid (0.118 g, 43%). LCMS: (M+H)+=255.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][OH:33])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:20][CH:19]=2)[CH:14]=[N:13]1)[CH3:11].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:10]([N:12]1[C:16](=[O:17])[N:15]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])=[CH:22][CH:23]=2)[CH:14]=[N:13]1)[CH3:11]
Reactant: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.5 %

Procedure:
2-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (8.26 g) was dissolved in 100 ml of ethyl acetate, to which 2.89 g of methanesulfonyl chloride and 2.54 g of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the solution was washed with water (20 ml×2) and 20 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 10 g of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9].[Cl:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([O:9][C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH3:3])[N:14]=[CH:13][N:12]=1
Reactant: C[C@@H]1CCC[C@H]1O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.22 g of trans-2-methylcyclopentanol was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring for 2 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.38 g of 4-chloro-6-(trans-2-methylcyclopentyloxy)pyrimidine.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)=[CH:14][C:13]=1[O:38][CH3:39])(=[O:10])=[O:9])[CH2:5][CH2:6][CH3:7].O.C(O)(=O)C>O1CCCC1.CO.O>[CH2:4]([S:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=2[O:33][CH2:34][CH:35]2[CH2:37][CH2:36]2)=[CH:14][C:13]=1[O:38][CH3:39])(=[O:9])=[O:10])[CH2:5][CH2:6][CH3:7]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)cc2OCC2CC2)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)O)cc2OCC2CC2)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.1 %

Procedure:
0.4 g (1 mmol) of lithium hydroxide monohydrate is added to a solution of 0.26 g (0.5 mmol) of corresponding methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-cyclopropylmethoxyphenyl)propanoate in 10 ml of a tetrahydrofuran/methanol/water mixture (5/1/1). The reaction medium is stirred at room temperature for 15 hours, treated with water, acidified to pH 4 with acetic acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue obtained is purified by chromatography on a column of silica eluted with a 97/3 dichloromethane/methanol mixture. 0.24 g (100%) of 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-3-cyclopropylmethoxyphenyl)propanoic acid is obtained in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.Cl.[CH:16]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>ClCCl>[CH:16]1([CH2:21][NH:22][C:12]([C:5]2[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CCCC1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carbonyl chloride (1.0 g, ex Maybridge) in dichloromethane (7 ml) at −2° was added a dropwise a solution of cyclopentanemethanamine hydrochloride (0.55 g) and triethylamine (1.4 ml) in dichloromethane (13 ml) and the solution stirred at 0° for 1 hour. Dichloromethane was removed under reduced pressure and ethyl acetate (20 ml) added. The solution was washed with 2N hydrochloric acid (3×15 ml), dried (MgSO4), evaporated and triturated with isohexane to afford 2-chloro trifluoromethyl-pyrimidin-5-carboxylic acid (cyclopentylmethyl)-amide (838 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([O:26]CC)=[O:25])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([OH:26])=[O:25])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@@H]3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CCC[C@@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 2A (2 g) and 0.1M lithium hydroxide (80 mL) in ethanol (100 mL) at 25° C. was stirred for 24 hours, adjusted to pH 3 with 1M hydrochloric acid, treated with water, and filtered.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:30][Mg]Br.CCOC(C)=O>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:21]=[CH:20][C:19]4[C:15](=[CH:16][N:17]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[N:18]=4)[CH:14]=3)([OH:12])[CH3:30])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc2cc(C(=O)c3cnc4ccc(Cl)nn34)ccc2n1
Reactant: C[Mg]Br
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc2nn(COCC[Si](C)(C)C)cc2c1)c1cnc2ccc(Cl)nn12
Reaction time: 0.5 h

Procedure:
To a solution of (6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-[2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-methanone (Stage 195.3, 539 mg, 1.259 mmol) in THF (50 mL) was added dropwise at rt a solution of methylmagnesium bromide in Et2O (3 M, 0.462 mL). After 30 min stirring, the RM was taken into EtOAc and washed with a 10% NaHCO3 solution and then with brine. The organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, n-hexane/EtOAc=95:5->0:100) to afford after recrystallisation in pentane with a little EtOAc the title compound as a light yellowish powder (tR 5.6 min (conditions 3), MH+=444).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Br.[CH3:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([N:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[CH3:6])[CH:3]1[O:5][CH2:4]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1CC1CO1
Temperature: 60 °C

Procedure:
Epibromohydrin (1.0 g, 7.6 mmole) was added to a stirred solution of 2-methylbenzimidazole (1.0 g, 7.6 mmole) and sodium hydride (0.3 g, 7.6 mmole) in anhydrous DMF (20 ml), and the mixture was heated at 60° C. under nitrogen for 0.5 hours. Water (100 ml) was added and the product extracted into CH2Cl2 (3×25 ml). The combined organics were washed with water (25 ml), brine (25 ml) and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave the crude product as a light yellow colored oil (1.4 g). This was purified by flash silica gel chromatography (10% methanol in CH2Cl2) to afford the titled product as a light oil (0.64 g, 45% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:67])[NH:4][C@@H:5]([CH:64]([CH3:66])[CH3:65])[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[NH:38][C:37]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:63])[C@@H:45]([NH:52]C(OCC6C=CC=CC=6)=O)[CH:46]6[CH2:51][CH2:50][S:49][CH2:48][CH2:47]6)=[N:36][CH:35]=5)=[CH:30][CH:29]=4)[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:7].Br>C(#N)C.CC(O)=O>[NH2:52][C@@H:45]([CH:46]1[CH2:47][CH2:48][S:49][CH2:50][CH2:51]1)[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:37]1[NH:38][C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:23]3[CH:24]=[C:25]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C:15]3[NH:14][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6](=[O:7])[C@@H:5]([NH:4][C:3](=[O:67])[O:2][CH3:1])[CH:64]([CH3:65])[CH3:66])=[N:17][CH:16]=3)[CH:27]=[CH:26]4)=[CH:29][CH:30]=2)=[CH:35][N:36]=1)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OCc6ccccc6)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Br
Solvent: CC#N
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@@H](N)C6CCSCC6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((S)-2-(benzyloxycarbonylamino)-2-(tetrahydro-2H-thiopyran-4-yl)acetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester (46 mg, 0.05 mmol) in ACN (0.4 mL) was add 33% HBr in HOAc (0.1 mL) and reaction mixture was cooled to 0° C. and then stirred for 2 hours. After concentrated to afford title compound as white solid (33 mg, 85%). MS (ESI) m/z 790 [M+H]+.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36]C1CCCCO1)[CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:17][C:18]([O:20][CH3:21])=[O:19].CC1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:22](=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC(CCCCCCCCOC1CCCCO1)=C(CCCCCCCCOC1CCCCO1)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC(CCCCCCCCO)=C(CCCCCCCCO)CC(=O)OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.7 %

Procedure:
A flamed-dried 20 mL vial fitted with screw-cap septa was charged with Dimethyl 3,4-bis(8-((tetrahydro-2H-pyran-2-yl)oxy)octyl)hex-3-enedioate (1 equiv, 0.855 mmol, 510 mg), MeOH (10 mL) and PTSA (0.1 equiv, 0.086 mmol, 16.4 mg). The reaction was stirred at rt for 14 h, quenched with sat. aq. NaHCO3, and diluted with CH2Cl2 (20 mL) and H2O (10 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with H2O (20 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash chromatography (65% EtOAc/Hex) to afford Dimethyl 3,4-bis(8-hydroxyoctyl)hex-3-enedioate (321 mg, 0.75 mmol, 88%) as an inseparable 2:1 mixture of isomers. TLC Rf=0.19 (50% EtOAc/Hex); 1HNMR (500 MHz): δ 3.61-3.70 (t plus two ovlp. s, 10H, J=6.7 Hz), 3.13 (s, 2.7H), 3.11 (s, 1.3H), 2.07-2.18 (4H), 1.57 (quint., 4H, J=7.8 Hz), 1.49 (bs, 2H), 1.26-1.40 (20H); 13CNMR (125 MHz): δ 174.4, 174.3, 130.7, 130.6, 62.99, 51.8, 37.6, 37.2, 33.2, 32.82, 32.75, 29.6, 29.5, 29.44, 29.35, 29.32, 28.3, 28.0, 25.71, 25.68; FTIR: 3375, 2926, 2854, 1736, 1434, 1332, 1242, 1192, 1155, 1048 cm−1; HRMS-ESI: calc. for C24H44NaO6 (M+Na)+: 451.3036. found: 451.3022.