Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]([F:39])([O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1)[CH:5]([F:27])[O:6][C:7]([F:26])([F:25])[C:8]([F:24])([O:13][C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:9]([F:12])([F:11])[F:10].Cl>O>[F:3][C:4]([F:39])([O:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1)[CH:5]([F:27])[O:6][C:7]([F:26])([F:25])[C:8]([F:24])([O:13][C:14]([F:22])([F:23])[C:15]([F:21])([F:20])[C:16]([F:18])([F:17])[F:19])[C:9]([F:12])([F:11])[F:10]
Reactant: COC(=O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)cc1

Procedure:
Water (500.0 mL) and potassium hydroxide were added to a round bottom flask equipped with a stirrer. Methyl 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoate (50.0 g, 0.0856 mol), as prepared in Example 11, was then added via the addition funnel and the reaction was placed in an oil bath and heated to a gentle reflux overnight. The flask was allowed to cool before acidifying with concentrated HCl, down to ph˜1.0. The precipitate was filtered and dried overnight. The solids were analyzed by proton NMR to be 4-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzoic acid.
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:27]I.CCOC(C)=O>C1COCC1>[I:27][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]=1
Reactant: II
Reactant: CCOC(=O)c1ncoc1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(I)oc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
To a solution of ethyl 5-phenyl-1,3-oxazole-4-carboxylate (Example 29, 0.921 mmol, 1 eq.) in THF (7 mL) at −78° C. was added a solution of lithium bis(trimethylsilyl)amide in THF (1M, 1.11 mmol, 1.2 eq.) dropwise by syringe. The resulting solution was stirred at −78° C. for 1 hour at which time a solution of iodine (1.38 mmol, 1.5 eq. in 2 mL THF) was added dropwise by a syringe. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for 1.5 hours. The resulting solution was poured onto 10% aqueous NaS2O3 (15 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, hexanes:EtOAc=9:1). The product was obtained as a pale yellow solid in 82% yield. MH+=344.0, Rf=0.31 (hexanes:EtOAc=6:1), retention time (LC-MS)=3.01 min.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:7]([CH:20]=1)[C:8]([N:10](CC)[CH:11](OC)[C:12](C)(C)C)=[O:9].I[Si](C)(C)C>C(Cl)Cl>[CH3:25][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([Si:21]([CH3:23])([CH3:22])[CH3:24])=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH3:12])=[O:9]
Reactant: CCN(C(=O)c1cc(N(C)C)ccc1[Si](C)(C)C)C(OC)C(C)(C)C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CCNC(=O)c1cc(N(C)C)ccc1[Si](C)(C)C
Reaction time: 2 h

Procedure:
The compound of Example 222 (0.31 g, 0.85 mmol) was dissolved in CH2Cl2 (20 mL) and was treated with iodotrimethylsilane (2.1 mL, 15 mmol) in a foil-covered flask. The reaction was stirred for 2 h and was quenched with sat NaHCO3. The mixture was extracted with ether, the organic layers were washed with brine and sat sodium bisulfite, dried (MgSO4) and concentrated to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallized from hexanes to afford 68 mg (5%) of the title compound as a white solid. m.p. 141-143° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]([CH3:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:10])[CH:3]=1.[N-:17]=[N+]=[N-].[Na+].CNCCNC>CS(C)=O.C(OCC)(=O)C.[Cl-].[NH4+].[Cu]I>[CH3:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([NH2:17])[CH:7]=[CH:6][N:5]=1)([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)CC(C)(C)Nc1cc(Br)ccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)CC(C)(C)Nc1cc(N)ccn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
A mixture of 4-bromo-N-(2,4,4-trimethylpentan-2-yl)pyridin-2-amine (7.5 g, 260 mmol), sodium azide (5.07 g, 780 mmol), CuI (1.4 g, 7.8 mmol), N,N′-dimethylethane-1,2-diamine (1.3 g, 15 mmol) in dimethylsulfoxide (150 mL) was heated in a sealed reaction vessel at 90° C. for 16 hours. The reaction mixture was diluted with ethyl acetate (500 mL), saturated ammonium chloride (1000 mL) and stirred for 1 hour. The organic layer was separated and the aqueous layer was again extracted with ethyl acetate (3×300 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated to give brown sticky mass which was purified by silica gel column chromatography using methanol and dichloromethane as eluent to yield 2 g (34%) of N2-(2,4,4-trimethylpentan-2-yl)pyridine-2,4-diamine.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CN1C(=O)CCC1>[NH2:25][C:22]1[CH:23]=[CH:24][C:18]2[N:17]=[C:16]([C:8]3[C:9]4[C:14]([NH2:15])=[N:13][CH:12]=[N:11][C:10]=4[N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:7]=3)[NH:20][C:19]=2[CH:21]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Agent: [Pd]
Solvent: CN1CCCC1=O
Product: Nc1ccc2nc(-c3cn(C4CCCC4)c4ncnc(N)c34)[nH]c2c1

Procedure:
7-Cyclopentyl-5-(6-nitro-1H-benzoimidazol-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1E, 1.0 g) was combined with 10% Palladium on carbon (100 mg) in 50 mL of anhydrous NMP and subjected to 50 psi of hydrogen at room temperature for 24 hours. LCMS monitor suggested pure desired product (M/Z 333.5, retention time 0.70 min. with analytical HPLC method 4). The mixture was filtered through celite. Desired product was used as an NMP stock solution (concentration of about 0.92 g in 45 mL).
Reaction SMILES: [C:1]1([N:11]2CCN[CH2:13][CH2:12]2)C2CCCCC=2C=C[CH:2]=1.[CH3:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:19]=1[NH2:20].Cl.ClCCNCCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:19]=1[N:20]1[CH2:13][CH2:12][NH:11][CH2:1][CH2:2]1
Reactant: c1cc2c(c(N3CCNCC3)c1)CCCC2
Reactant: Cc1cc(C)c(N)c(C)c1
Agent: Cl
Agent: ClCCNCCCl
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: Cc1cc(C)c(N2CCNCC2)c(C)c1
Yield: 55 %

Procedure:
Compound 31A is prepared according to the procedure described for compound 26A, using the following reactants: 2,4,6-trimethylaniline (4.8 ml, 34 mmol); bis(2-chloroethyl)amine hydrochloride (6.05 g, 34 mmol); sodium carbonate (1.8 g, 17 mmol); 1-butanol (75 ml). After impregnating onto silica, the crude reaction product is purified by flash chromatography with a mixture (95/5/1) and then (90/9/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[C:17]2[O:16][CH2:15][CH2:14][O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-])=O>[Pd].CO>[O:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([NH2:5])[C:17]=2[O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1cccc2c1OCCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1cccc2c1OCCO2
Yield: 74 %

Procedure:
Ammonium formate (3.40 g, 0.054 mol) and 10% palladium on charcoal (1.44 g) were added to a stirred solution of the product of example 12 (2.45 g, 0.0135 mol) in methanol (15 ml). After the considerable effervescence had ceased, the mixture was filtered, evaporated in vacuo and triturated with acetonitrile. The residue was purified by chromatography (silica; ether) to give the product (1.51 g).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[OH:38])=[O:30]>C(N(CC)CC)C>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=3[OH:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1ccc(O)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(O)cc2O)CC1
Yield: 18.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (3.87 g) as a starting compound, 6-bromo-1-(2,4-dihydroxyphenyl)-1-hexanone (3.00 g) and triethylamine (6.5 ml) were reacted and purified in the same manner as in Example 172 to give 0.97 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2,4-dihydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide, m.p. 96°-99° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:35]=[CH:34][C:33]([O:36][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:32][C:27]=2[S:28][C:29]=1[CH2:30][CH3:31])=[O:24]
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc2c1C(=O)NC
Yield: 9.8 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (155 mg, 0.5 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (141 mg, 0.60 mmole) and Cs2CO3 (488 mg, 1.5 mmole) in a manner analogous to that described for example 1 to give a yellow solid (25 mg, 10%). 1H NMR (DMSO-d6, 300 MHz), δ8.59 (1H, d, J=5.56 Hz), 8.33 (1H, d, J=4.55 Hz), 8.03 (1H, s), 7.99 (1H, d, J=2.02 Hz), 7.81 (1H, d, J=8.59 Hz), 7.33 (1H, dd, J=2.27, 8.84 Hz), 6.77 (1H, d, J=5.56 Hz), 4.31 (1H, br s), 3.90-3.81 (2H, m), 3.37-3.15 (2H, m), 3.37 (3H, s), 3.00 (2H, q, J=7.41 Hz), 2.83 (3H, d, J=4.55 Hz), 2.09-1.84 (4H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCC2C=CC(CO)=CC=2)C=CC=CC=1.[N:36]([C@H:39]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:40]([O-:42])=[O:41])=[C:37]=[O:38].[N-]=C=O.COC(=O)[C@H](CC1C=CC=CC=1)N>>[C:44]1([CH2:43][CH:39]([NH:36][C:37]([O:16][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][CH:17]=2)=[O:38])[C:40]([OH:42])=[O:41])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C=N[C@H](Cc1ccccc1)C(=O)[O-]
Reactant: O=C(O)c1ccc(CCCc2ccccc2)cc1
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: OCc1ccc(CCCc2ccccc2)cc1
Agent: [N-]=C=O
Product: O=C(NC(Cc1ccccc1)C(=O)O)OCc1ccc(CCCc2ccccc2)cc1

Procedure:
3-Phenyl-2-[4-(3-phenyl-propyl)-benzyloxycarbonylamino]-propionic acid 168, mp. 134.8-135.2° C. was prepared from 4-(3-phenyl-propyl)-benzoic acid (commercially available from Aldrich) followed by reduction to [4-(3-phenyl-propyl)-phenyl]-methanol, condensation with (R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolysis as described for example in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1/[CH:20]=[CH:21]/[C:22](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:22]1/[CH:21]=[CH:20]/[C:16]1[S:15][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)/C=C/c1cccs1
Reactant: Nc1ccccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1cccs1

Procedure:
The titled compound was prepared from N-(2-pyridyl)-o-phenylenediamine and (E)-3-(2-thienyl)acryloyl chloride (Aitken, R. A.; Boeters, C.; Morrison, J. J. J. Chem. Soc. Perkin. Trans. I, 1994, 17, 2473) according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O1CCCC1.CCOCC>[CH2:24]([O:23][C:21]([NH:1][C@@H:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][NH:4][C:3]1=[O:13])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@@H]1Cc2ccccc2CNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(N[C@@H]1Cc2ccccc2CNC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.8 %

Procedure:
A solution of 210 mg (1.19 mmol) of 4(R)-amino-2,3,4,5-tetrahydro-1H-2-benzazepin-3-one in 5 mL of tetrahydrofuran was treated with 5 mL of 10% aqueous potassium carbonate followed by 0.20 mL (0.24 g, 1.3 mmol, 1.1 eq) of 95% benzyl chloroformate. The mixture was stirred vigorously at room temperature for 6 hours then diluted with 20 mL of ether and the mixture transferred to a separatory funnel. The lower aqueous layer was removed and washed with several portions of ether. The combined ether washes and ether layer were washed, with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and solvents removed under vacuum to give 365 mg (1.14 mmol, 96%) of the product. 1H NMR (400 MHz, CDCl3): δ3.08 (dd; 12, 16 Hz; 1H), 3.27 (dd; 7, 16 Hz; 1H), 4.06 (d, 16 Hz, 1H), 4.75 (d, 16 Hz, 1H), 5.00 (dd; 7, 12 Hz; 1H), 5.12 (s, 2H), 7.1-7.4 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9](=O)[NH:10][C:4]=2[CH:3]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([N:28]3[CH2:29][CH2:30][N:25]([CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:26][CH2:27]3)=[N:10][C:4]=2[CH:3]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Nc2cc(Cl)ccc2Oc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)N=C(N1CCN(Cc3ccccc3)CC1)c1ccccc1O2
Temperature: 25 °C
Yield: 95.6 %

Procedure:
To a stirred solution of 8-chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepin-11-one (0.3 g; 1.22 mmol) in dry toluene (10 mL) at room temperature was added 1-benzyl piperazine (1.0 mL; 5.61 mmol; Aldrich) followed by the dropwise addition of TiCI4 (1M in toluene, 1.47 mL; 1.47 mmol). The reaction mixture was refluxed for 2 hours, cooled to room temperature and then poured into an ammonium hydroxide solution (30%, 50 mL). The resulting mixture was extracted with dichloromethane (4×50 mL), and the combined organic phases were then dried (K2CO3) and concentrated. Purification of the product was conducted on silica gel using ethyl acetate:hexane (5:1→4:1) as the eluant to give 0.471 g (95%) of the title compound as a yellow solid; m.p. 50°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:21])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C([O:24][C:25]([C:27]12[CH2:44][CH:43]1[CH:42]=[CH:41][CH2:40][CH2:39][CH2:38][CH2:37][N:36]([CH3:45])[C:35](=[O:46])[N:34]1[CH:30]([CH2:31][CH:32](O)[CH2:33]1)[C:29](=[O:48])[NH:28]2)=[O:26])C>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:21][CH:32]3[CH2:31][CH:30]4[N:34]([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH:42][CH:43]5[C:27]([C:25]([OH:26])=[O:24])([NH:28][C:29]4=[O:48])[CH2:44]5)[CH2:33]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Reactant: COc1ccc2c(O)nc(-c3cccc(C)n3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3cccc(C)n3)nc2c1C
Yield: 11.6 %

Procedure:
Quinazolinol derivative (117) (198 mg, 0.7 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (50 mg, 10%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[C:11]([CH3:39])([CH3:38])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24](OCC)=[O:25])C.O.[OH-].[Na+]>CC(OC)(C)C>[CH3:38][C:11]([CH3:39])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:30])[CH2:24][OH:25])[CH2:10][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCC(CCCCCC(C)(C)C(=O)OCC)OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(CO)CCCCCC(CCCCCC(C)(C)CO)OC1CCCCO1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Under nitrogen atmosphere, LiAlH4 (2.2 g, 58 mmol) was suspended in anhydrous MTBE (250 mL) and cooled with an ice/water bath. 2,2,14,14-Tetramethyl-8-(tetrahydropyran-2-yloxy)-pentadecanedioic acid diethyl ester (12.0 g, 24.7 mmol) in anhydrous MTBE (100 mL) was added dropwise over 1.5 h. This mixture was left overnight at ambient temperature. After the reaction was completed, deionized water (4 mL) was added followed by 20% aqueous NaOH solution (5 mL) and water (14 mL). The ether solution was decanted from the formed white residue. The residue was washed with MTBE (4×20 mL) and the combined ether solutions were dried over MgSO4. The solvent was removed under reduced pressure to give crude 2,2,14,14-tetramethyl-8-(tetrahydropyran-2-yloxy)-pentadecane-1,15-diol as a colorless oil (8.9 g, 90%), which was used without further purification. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.72-4.59 (m, 1H), 4.03-3.84 (m, 1H), 3.69-3.38 (m, 2H), 3.31 (s, 4H), 2.00-1.15 (m, 28H), 0.87 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 97.38, 76.57, 71.83, 62.65, 38.55, 34.96, 34.84, 33.33, 31.17, 30.75, 30.63, 26.92, 25.52, 24.95, 23.84, 23.70, 19.96. HRMS (EI, POS): Calcd for C24H48O4 (M+): 400.3553. found: 400.3564.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([OH:16])([C:14]#[CH:15])[C:10]([F:13])([F:12])[F:11].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18]>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:17](=[O:18])[O:16][C:9]([C:14]#[CH:15])([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C#CC(O)(c1cc(Cl)ccc1N)C(F)(F)F
Solvent: C1CCOC1
Product: C#CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21
Temperature: 60 °C

Procedure:
A THF solution of 2-(2-amino-5-chlorophenyl)-1,1,1-trifluoro-3-butyn-2-ol (5.0 g, 20.0 mmol in 225 mL THF) was treated with 1,1'-carbonyldiimidazole (13.0 g, 80.0 mmol) and heated in an oil bath at 60° C. for 17 h. The THF was removed in yacuo, the residue dissolved in ethyl acetate then washed with 10% citric acid, sodium bicarbonate, water and brine before drying over sodium sulfate. Following filtration and evaporation in vacuo the crude product was isolated (3.6 g) and recrystallized from ethyl acetate: hexane. The product (+/-) 6-chloro-4-ethynyl-4-(1,1,1-trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one was isolated as a white crystalline solid (3.22 g, 58.4% yield): mp 226°-227° C. 1H-NMR (CDCl3 +trace DMSO): δ3.16 (s, 1H), 6.98 (d, J=3.3 Hz, 1H), 7.35 (m, 1H), 7.51 (s, 1H), 10.66 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.01 min, m/z=416.21; 1H NMR (CD3OD) 1.30 (m, 1H), 1.55 (d, 3H), 1.62 (m, 1H), 1.94 (m, 2H), 2.20 (m, 1H), 2.32 (m, 1H), 2.48 (m, 1H), 3.09 (m, 1H), 3.44 (m, 2H), 5.57 (m, 1H), 7.03 (d, 2H), 7.29-7.40 (m, 6H), 7.67 (d, 2H), 7.73 (d, 1H), 7.84 (t, 1H), 8.55 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>C(Cl)(Cl)Cl>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]([NH:1][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[N:11][CH:10]=1
Reactant: CCN=C=O
Reactant: COC(=O)c1cc(N)ncc1Br
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1cc(C(=O)OC)c(Br)cn1
Temperature: 40 °C
Yield: 99.9 %

Procedure:
Methyl 2-amino-5-bromoisonicotinate (200 g, 865 mmol) was dissolved in chloroform (1.2 L) and placed into a 2 L Parr apparatus. Ethyl isocyanate (204 mL, 2.59 mol) was added, and the Parr apparatus was heated at 40° C. for 36 h at which time the reaction was determined to be complete. The mixture was then cooled to room temperature, concentrated, and the solid was dissolved in 2:1 ethyl acetate: tetrahydrofuran (3 L). This solution was extracted with water (1 L), and the water was back extracted with ethyl acetate (300 mL). The organic layers were combined then dried over sodium sulfate, filtered, and concentrated yielding 261 g (quant) of methyl 5-bromo-2-(3-ethylureido)isonicotinate as a dark yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.Cl.[Br:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])=[C:15]([NH:20][C:21](=O)[CH2:22][O:23][CH2:24][CH3:25])[CH:16]=[N:17]2)=[N:12][CH:11]=1>C(O)C>[Br:9][C:10]1[CH:11]=[N:12][C:13]2[C:14]3[N:27]([CH2:28][C:29]([CH3:31])([OH:32])[CH3:30])[C:21]([CH2:22][O:23][CH2:24][CH3:25])=[N:20][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)O
Temperature: 77 °C
Yield: 90.9 %

Procedure:
Potassium carbonate (113 g) and deionized water (565 mL) were sequentially added to a solution of N-{7-bromo-4-[(2-hydroxy-2-methylpropyl)amino][1,5]naphthyridin-3-yl}-2-ethoxyacetamide hydrochloride (113 g, 261 mmol) in denatured ethanol (1.695 L), and the resulting mixture was heated at reflux (77° C.) overnight and allowed to cool to room temperature. The ethanol was removed under reduced pressure, and the resulting mixture was filtered to isolate a solid. The solid was washed with deionized water (100 mL) and dried over two nights in a vacuum oven at 40° C. to provide 90 g of 1-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol as a brown solid. Material from a separate run was used in the next step.