Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:40]([OH:42])=O)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].Cl.[CH2:44]([NH:50][CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[C:25]([CH3:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:21]=3)[CH2:16][CH:15]2[C:40](=[O:42])[N:50]([CH2:44][CH2:45][CH2:46][CH2:47][CH:48]=[CH2:49])[CH3:51])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reactant: C=CCCCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Reaction time: 3 h
Yield: 76 %

Procedure:
Compound 156 (0.81 g, 1.40 mmol) and hex-5-enyl-methyl-amine hydrochloride (272 mg, 1.82 mmol) was dissolved in dry DMF (50 mL). DIEA (975 μL, 5.6 mmol) was added and the reaction flask was placed in an ice bath. After 10 minutes HATU (559 mg, 1.47 mmol) was added to the solution. The reaction flask was allowed to reach room temperature and the stirring was continued for 3 hrs before the solvent was removed by evaporation. The crude product was extracted with CHCl3 and washed with saturated NaHCO3 (aq). The organic phase was dried (Na2SO4), evaporated on silica and purified to by flash chromatography (heptane:ethyl acetate 1:1) to give the title compound (0.716 g, 76%), LRMS (M+H) 673.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([CH3:22])[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:12]=2)=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(O)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(OC(C)=O)c([N+](=O)[O-])c1
Reaction time: 5 h

Procedure:
A mixture of 1.5 g of ethyl 4-(4-hydroxy-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate and 7.5 ml of acetic anhydride in 7 ml of tetrahydrofuran was stirred for 5 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1). The fractions containing the desired product were combined and concentrated in vacuo. The crystalline residue was recrystallized from diethyl ether to give ethyl 4-(4-acetoxy-5-nitrophenyl)-6-methyl-2-phenyl-5-pyrimidinecarboxylate (0.23 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=O.[NH2:23][OH:24].Cl.C([O-])(=O)C.[NH4+]>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[N:23][OH:24]
Reactant: NO
Reactant: O=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: ON=C(c1ccc(F)cc1F)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
To the compound (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone (22 g) in 95% ethanol (350 ml) and water (100 ml) was added NH2OH.HCl (10.1 g) and ammonium acetate (12.7 g, 2.1 eq). The resulting mixture was refluxed for 3.5 hours. The mixture was then allowed to stir at room temperature for 24 hours. The reaction mixture was concentrated to remove ethanol, poured into water (500 ml), and extracted with dichloromethane (500 ml). This was followed by washing with water, brine, and drying over magnesium sulfate. The product was concentrated to an oil and purified by column chromatography to yield 12 g of (2,4-difluorophenyl)[1-(phenylmethyl)-3-pyrrolidinyl]methanone oxime.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: CCC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A stirred and cooled solution of 2-bromo-6-ethyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (1.13 g, 2.46 mmol) and cyclohexene (2.5 mL, 24.6 mmol) in dichloromethane (5 mL) was treated drop-wise under nitrogen at −30° C. with boron tribromide (2.5 mL, 24.6 mmol). After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for four hours. The reaction was cooled to −30° C. and quenched with methanol (1 mL). The solvent was removed in vacuo to yield the title compound as a gray powder (0.982 g, 2.21 mmol, 90%), which was confirmed by LCMS (ES−, FA, CV=20 or 5).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[F:22])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[F:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COc1ccc(C2=CCN(Cc3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCNCC2)c(F)c1
Reaction time: 48 h

Procedure:
A solution of 1-benzyl-4-(2-fluoro-4-methoxyphenyl)1,2,3,6-tetrahydropyridine (Step B; 117 mg; 0.393 mmol) in MeOH (10 mL) was treated with a catalytic amount of 10% Pd/C and the reaction was placed under an atmosphere of H2 (Parr Shaker; 45 PSI) for 48 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 4-(2-fluoro-4-methoxyphenyl)piperidine as a tan solid. LCMS=210.1 (M+1)+. 1 H NMR (CDCl3, 500 MHz) δ 7.16 (t, J=8.7 Hz, 1 H), 6.68 (dd, J=8.7, 2.5 Hz, 1 H). 6.60 (dd, J=12.3, 2.5 Hz, 1 H), 3.78 (s, 3 H), 3.63 (d, J=12.6 Hz, 2 H), 3.09-2.98 (m, 2 H), 2.18 (q, J=12.1 Hz, 2 H), 2.02 (d, J=13.3 Hz, 2 H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:18]=[CH:17][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].[F:21][C:22]([F:26])=[C:23]([Cl:25])[Cl:24].O>C(#N)C>[Cl:24][CH:23]([Cl:25])[C:22]([F:26])([F:21])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:8]2[CH:17]=[CH:18][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(O)cc2)cc1
Reactant: FC(F)=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)C(Cl)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 5.29 g (0.0200 mole) of 4-(4-(methylsulfonyl)phenoxy)phenol (Example 21) in 100 ml of acetonitrile was added 0.80 g (0.0200 mole) of NaOH. The mixture was stirred at room temperature for 1 hr and then cooled to 3° C. in an ice bath. To the cold slurry was slowly added 4.0 g (0.0300 mole) of 1,1-difluoro-2,2-dichloroethylene dissolved in 15 ml of acetonitrile and the reaction mixture stirred at 3°-5° C. for 3 hrs. To the cold mixture 150 ml of water was added which resulted in the product precipitating as an oil. The product was extracted from the mixture with CH2Cl2. The organic layer was washed with water, dried (Na2SO4) and solvent rmoved in vacuo, which gave 7.1 g (89.4% yield) of product. Purification was accomplished by column chromatography using silica gel as the support and chloroform as the eluent, which afforded purified 1 -(2,2-dichloro-1,1-difluoroethoxy)-4-(4-(methylsulfonyl)phenoxy)benzene, mp 67°-70° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.FC(F)(F)C(O)=O>CCOCC>[NH2:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
7β-(t-Butoxycarbonyl)amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (2.2 g) is dissolved in ice cooled solution of trifuoroacetic acid (20 ml) and the mixture is stirred for 20 minutes. Then trifluoroacetic acid is taken off under reduced pressure and viscous residue is obtained. The residue becomes solid upon addition of ether (50 ml). The solid is triturated, collected by filtration, washed with ether and dried over phosphorus pentoxide. The procedure provides 7β-amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (1.55 g).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][NH:40][CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:48](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:37][CH2:36][N:35]4[CH2:38][CH2:39][N:40]([CH3:48])[CH2:41][CH:34]4[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:1])[F:45])[CH:8]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc(F)ccc1-c1cc(N2CCN3CCNCC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCN(C)CC3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of crude 2-[3,5-bis(trifluoromethyl)phenyl]-N-[4-(4-fluoro-2-methylphenyl)-6-(octahydro-2H-pyrazino[1,2-a]pyrazin-2-yl)-3-pyridinyl]-N,2-dimethylpropanamide (D80, 100 mg, 0.16 mmol) in 5 mL of acetonitrile was added a 37% aqueous formaldehyde solution (24 μL, 0.32 mmol). The solution was stirred at room temperature for 30 min, and then sodium triacetoxyborohydride (50 mg, 0.24 mmol) was added and the reaction stirred at room temperature overnight. The solvent was evaporated and the residue dissolved in dichloromethane and extracted with water and brine. The product was purified by flash chromatography (silica, dichloromethane to dichloromethane: MeOH 95:5). Obtained 58 mg of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:38])([CH3:37])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][C:20](=[CH:23][C:24](OCC)=O)[CH2:19][CH2:18]2)[CH:9]=1.C(CP(=O)(OCC)OCC)#[N:40]>>[CH3:36][Si:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:38])([CH3:37])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:18][CH2:19][C:20](=[CH:23][C:24]#[N:40])[CH2:21][CH2:22]2)[CH:9]=1
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: CCOP(=O)(CC#N)OCC
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=CC#N)CC2)nc2ccnn12

Procedure:
2-(4-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate, but with diethyl cyanomethylphosphonate substituted for triethyl phosphonoacetate.
Reaction SMILES: [NH3:1].[ClH:2].[I:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7](=[NH:11])OCC>C(O)C>[ClH:2].[I:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([NH2:11])=[NH:1]
Reactant: N
Reactant: CCOC(=N)c1cccc(I)c1
Agent: Cl
Solvent: CCO
Product: N=C(N)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ammonia gas was bubbled into an ice-cold suspension of the product (1.00 g, 3.21 mmol) from Step A in 20 mL of absolute ethanol for 20 min. The resultant clear solution was allowed to warm to room temperature and stirred for 48 h. The reaction mixture was then concentrated under reduced pressure, and the residue was triturated with diethyl ether. The supernatant was decanted, and the residual gummy product was dried in vacuo to afford the title compound as white foam.
Reaction SMILES: O=C1[N:6](CC(OC(C)(C)C)=O)[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18]C=2N1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[NH:27][C:26](=[O:28])[N:25]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[C:24]=2[CH:37]=1>>[Br:19][C:20]1[CH:21]=[CH:22][C:23]2[N:27]([C:18]3[CH:17]=[CH:16][CH:15]=[CH:5][N:6]=3)[C:26](=[O:28])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]=2[CH:37]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccc(Br)cc21
Product: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccc(Br)cc21

Procedure:
Essentially following the procedures described for Intermediate 4, but using tert-butyl (6-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=348 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: COc1ccc(CNc2ccc(O)c(C(=O)O)c2)cc1
Yield: 49.9 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (1.00 g, 6.53 mmole) and 4-methoxybenzyl chloride (1.23 g, 7.84 mmole), 890 mg (50% yield) of 5-(4-methoxybenzyl)aminosalicylic acid was obtained as a white solid.: mp 205-206° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]1([C:16]2([C:19]3[N:24]=[C:23]4[S:25][C:26]([C:28]5[CH:35]=[CH:34][C:31]([C:32]#N)=[CH:30][CH:29]=5)=[N:27][C:22]4=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(C(C(C([O-])=O)O)O)([O-])=[O:37]>C(Cl)Cl>[C:10]1([C:16]2([C:19]3[N:24]=[C:23]4[S:25][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH:32]=[O:37])=[CH:30][CH:29]=5)=[N:27][C:22]4=[CH:21][CH:20]=3)[CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: N#Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
DIBAL-H (1.0M in hexanes) (185 μl, 0.185 mmol) was added to a solution of 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzonitrile (59.6 mg, 0.169 mmol) in DCM (2.7 mL) at 25° C., and the resulting solution was stirred at 25° C. for 45 min. Sat. aq. Na/K tartrate solution (3.0 mL) was added, and the resulting mixture was vigorously stirred for 15 min, then partitioned between DCM (40 mL) and sat. aq. Na/K tartrate solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc/Hexanes) provided 4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde as a light yellow solid. MS (ESI) m/z: Calculated: 356.1; Observed: 357.1 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:8]=[N:7]1)C.[OH-].[Na+].C.OS([O-])(=O)=O.[Na+]>O.CCOC(C)=O>[OH:16][C:11]1([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:17])=[O:3])[CH:10]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)Cn1cc(C2(O)CCCC2)nn1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)Cn1cc(C2(O)CCCC2)nn1
Yield: 87 %

Procedure:
To a solution of ethyl[4-(1-hydroxycyclopentyl)-1H-1,2,3-triazol-1-yl]acetate (Preparation 293, 36.4 g, 151 mmol) in water (50 mL), was added a solution of NaOH (7.60 g, 190 mmol) in water (25 mL). The solution was refluxed with activated charcoal, filtered through Celite, and NaHSO4 (25.8 g, 190 mmol) added. EtOAc (50 mL) was added to the filtrate. The formed precipitate was separated by filtration, dissolved in EtOAc (100 mL), and the solution was filtered. The water layer was extracted with EtOAc (10×50 mL), and the combined extracts were evaporated to a volume of 100 mL. The precipitate was filtered, washed with ethyl acetate (2×50 mL), and concentrated under reduced pressure to afford the title compound as a colorless crystalline substance in 87% yield, 27.8 g. mp 124.0-126.0° C.; MS m/z 212 [M+H]+
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][OH:5].[C:37](OC(=O)C)(=[O:39])[CH3:38].O>N1C=CC=CC=1>[C:37]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:36])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:35])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:34])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:39])[CH3:38]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)CCO
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reaction time: 1 h

Procedure:
3.5 g of 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol was dissolved in 20 ml of pyridine, and 10 ml of acetic anhydride was added. After 20 g of iced water was added, the solution was stirred for one hour and extraction was then made using 100 ml of n-hexane. The extract was washed with 1N hydrochloric acid and then with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenyl acetate in a colorless oily form.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=1.[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][NH:42][C@@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:40]([O:39][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:47])=[CH:21][CH:22]=2)[C:6](=[O:23])[CH:5]=[CH:4][C:3]=1[C:24](=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[C:27]([CH3:32])[CH:26]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: Cc1cc(C(=O)c2ccc(=O)n(-c3ccc(OCCCOS(C)(=O)=O)cc3)c2N)ccc1F
Product: Cc1cc(C(=O)c2ccc(=O)n(-c3ccc(OCCCN[C@@H](CC(C)C)C(=O)OC4CCCC4)cc3)c2N)ccc1F

Procedure:
From Intermediate 4A and L-leucine cyclopentyl ester (Intermediate 8), LCMS purity 89%, m/z 578 [M+H]+, 1H NMR (400 MHz, d6-DMSO), δ: 0.95 (6H, m), 1.55-2.25 (12H, m), 2.30 (3H, m), 2.75-3.30 (2H, m), 4.15 (3H, m), 5.25 (1H, m), 5.70 (1H, d). 7.15 (2H, d), 7.30-7.40 (4H, m), 7.40-7.50 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]C)=[O:35])[CH:28]=[CH:27]4)=[CH:20][CH:19]=2)=[C:12]([CH:38]([CH3:40])[CH3:39])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[CH:27]4)=[CH:22][CH:23]=2)=[C:12]([CH:38]([CH3:40])[CH3:39])[O:11][N:10]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCCCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCCOc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 87.5 %

Procedure:
To a solution of methyl 6-[4-({3-[3-(2,6-dichlorophenyl) -5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylate (14 mg, 0.024 mmol) in 1:1 tetrahydrofuran:methanol (1 mL) was added 1 N sodium hydroxide (0.089 mL, 0.089 mmol). The solution was heated in a microwave reactor at 90° C. for 10 minutes. Then 1 N hydrochloric acid (0.089 mL, 0.089 mmol) was added and the mixture was concentrated. Water and ethyl acetate were added to the residue and the layers were separated. The ethyl acetate layer was dried over magnesium sulfate and concentrated to afford 12 mg of 6-[4-({3-[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]propyl}oxy)phenyl]-2-quinolinecarboxylic acid as a yellow solid (0.021 mmol, 89%). 1H-NMR (400 MHz, DMSO-d6) δ 8.42 (d, J=9 Hz, 1H), 8.28 (d, J=9 Hz, 1H), 8.19 (d, J=9 Hz, 1H), 8.06-8.04 (m, 2H), 7.64 (d, J=9 Hz, 2H), 7.41-7.29 (m, 3H), 6.93 (d, J=9 Hz, 2H), 3.90 (t, J=6 Hz, 2H), 3.20 (septet, J=7 Hz, 1H), 2.52 (t, J=6 Hz, 2H), 1.83-1.77 (m, 2H), 1.34 (d, J=7 Hz, 6H). HRMS (ESI) C31H26Cl2N2O4 calculated: 561.1342 (M+H)+, found: 561.1344 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6]([O:11][Si](C)(C)C)([C:9]#[N:10])[CH2:5][CH2:4]1.Cl.S([O-])(O)(=O)=O.[Na+]>O>[OH:11][C:6]1([C:9]#[N:10])[CH2:5][CH2:4][N:3]([O:2][CH3:1])[CH2:8][CH2:7]1
Reactant: CON1CCC(C#N)(O[Si](C)(C)C)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CON1CCC(O)(C#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-Methoxy-4-trimethylsilanyloxy-piperidine-4-carbonitrile (1.0 g, 4.4 mmol) was slowly added to aqueous HCl (3N) at 15° C. The mixture was stirred for two hours at room temperature and then poured into cold (0° C.) water. Sodium hydrogen sulfate (saturated aqueous solution) was slowly added to adjust the pH to 7. The aqueous layer was carefully extracted with ethyl acetate three times. All organic layers were combined, dried over magnesium sulfate and concentrated. The crude product (ca 94% pure) was used directly for the next step without further purification. Yield: 500 mg of 4-hydroxy-1-methoxy-piperidine-4-carbonitrile (compound P4.2) as light yellow solid.