Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)=[N:9]1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH2:34][CH3:35])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:9]=2)[N:18]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
107.35 mg (0.31 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4,5,6-pyrimidinetriamine trihydrochloride from Example 8A are added to 5 ml of pyridine, and the mixture is cooled to 0° C. 33.25 mg (0.31 mmol) of ethyl chloroformate are added, and the reaction is left to stir at RT overnight. The pyridine is evaporated in vacuo in a rotary evaporator, and the residue is purified by preparative RP-HPLC.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:26]2[S:22][C:23](=[O:28])[NH:24][C:25]2=[O:27])=[CH:16][CH:15]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(OCCNc2nc3ccccc3o2)cc1
Product: O=C1NC(=O)C(=Cc2ccc(OCCNc3nc4ccccc4o3)cc2)S1

Procedure:
The title compound (m.p. 242°-5° C.) was prepared from 4-[2-(N-(2-benzoxazolyl)amino)ethoxy]benzaldehyde (5.18 g) and 2,4-thiazolidinedione (2.36 g) by a similar procedure to that described in Example 4.
Reaction SMILES: [Cl:1][CH:2]1[CH:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2-].[Na+].N>C1COCC1.CCOCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]#[C:9][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CC1CCCCC1Cl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: [NH2-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Clc1ccccc1C#CC1CCCCC1
Reaction time: 72 h

Procedure:
3-Chloro-4-cyclohexylacetophenone (0.25 moles) and phosphorus pentachloride (0.31 moles) are placed in a 3-necked flask equipped with a mechanical stirrer, a condenser connected to a nitrogen inlet, and a thermometer. The mixture is stirred at 33°-35° C. for 3 days. The cooled reaction mixture is poured onto 800 g. of ice and extracted with 3× 500 ml. of ether. The ether fraction is washed with 2× 100 ml water 4× 100 ml of 5% sodium hydroxide, 3× 50 ml water, 2× 50 ml of saturated saline and dried over sodium sulfate. The ether is removed to give the chlorinated intermediate. The intermediate is dissolved in anhydrous THF (200 ml) and is added dropwise to a freshly prepared solution of sodamide in liquid ammonia, using a dry-ice condenser. The reaction mixture is allowed to stir at room temperature overnight; then, it is poured into 50 ml of water and 500 ml of ether. The ether fraction is washed with 3× 50 ml water and 50 ml of saturated saline and is dried over sodium sulfate. Removal of solvent gives a residue which is distilled to give 3-chloro-4-cyclohexylethynylbenzene.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[NH2:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1.C(O)(C(F)(F)F)=O>C(O)(C)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[C:12]1[C:11]2[CH:10]=[C:9]([NH2:8])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: O=Cc1cccs1
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)C(=Cc1cccs1)c1ccccc1-2

Procedure:
2-Thiophenecarboxaldehyde (80.4 mg, 0.72 mmol) was added to 2-aminofluorene (100 mg, 0.55 mmol) and refluxed in isopropanol for 12 hours with a catalytic amount of TFA. The solvent was evaporated and the product was purified by flash chromatography using anhydrous basic activated alumina gel (AlO2) and 40% ethyl acetate and 60% hexanes. The title compound was obtained as a yellow product. (45.4 mg, 0.165 mmol, 30%). M.p.: 143° C. 1H-NMR (300 MHz, [D] DMSO): δ=8.65 (s, 1H), 7.89 (t, 2H, 3J=10.9 Hz), 7.81 (d, 1H, 3J=6.7 Hz), 7.69 (dd, 1H, 3J=4.8 Hz, 4J=1.4 Hz), 7.57 (d, 1H, 3J=9.76 Hz), 7.50 (s, 1H), 7.37 (t, 1H, 3J=9.88 Hz), 7.32 (t, 2H, 3J=11 Hz), 7.22 (dd, 1H, 3J=4.84 Hz, 4J=1.8 Hz), 3.94 (s, 2H). 13C-NMR (300 MHz, [D] DMSO): δ=152.9, 148.4, 144.2, 143.1, 144.4, 141.0, 129.7, 128.8, 128.2, 128.4, 127.4, 127.1, 126.8, 125.8, 123.6, 120.3, 36.5. C.V. −1.36, −0.96, −0.56, −0.02, 0.62, 1.39 V. In 0.1 M TBAPF6 as supporting electrolyte in degassed anhydrous acetonitrile λmax=352 nm. λem=302 nm. Eg=454 nm, 62.95 Kcal/mol. ΔE=300 nm, 95.26 Kcal/mol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].S(=O)(=O)(O)[OH:18].OO>C(O)(=O)C>[N+:1]1([O-:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccnc1C(=O)OCC
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc[n+]([O-])c1C(=O)OCC

Procedure:
A mixture of 99 g of diethyl pyridine-2,3-dicarboxylate, 7.2 mL of concentrated sulfuric acid, 85 mL of 30% hydrogen peroxide and 256 mL acetic acid is stirred and heated at 85° for 4 hours. The reaction is concentrated in vacuo, and the residue is dissolved in methylene chloride, and washed with water, then saturated sodium bicarbonate. After drying, the organic phase is concentrated in vacuo to afford 79 g of the desired product, mp 80°-85°. A portion recrystallized from carbon tetrachloride-pentane has mp 87°-88°.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[S:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:27]3[S:21][C:22](=[S:23])[NH:24][C:25]3=[O:26])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CSC(=S)N1
Reactant: CC(C)(C)c1ccc(COc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(COc2ccc(C=C3SC(=S)NC3=O)cc2)cc1

Procedure:
The 4-[(4-t-butyl)benzyloxy]benzaldehyde (2.6 g, 9 mmol) was then coupled with rhodanine (1.4 g, 10.5 mmol) by adding the reactants to sodium acetate (2.9 g, 36 mmol) and acetic acid. The reaction mixture was then heated to reflux and refluxed overnight.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[O:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]([NH2:18])[C:11]3=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:4]([Cl:28])[CH:3]=1.CCN(CC)CC.[Br:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:36][CH2:37][CH2:38][CH2:39][C:40]([NH:18][CH:17]1[C:11]2[C:12](=[N:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[Cl:28])=[C:9]([C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[CH:10]=2)[O:14][C:15]([CH3:20])([CH3:19])[CH2:16]1)=[O:41]
Reactant: O=C(Cl)CCCBr
Reactant: CC1(C)CC(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(NC(=O)CCCBr)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Br)cc3Cl)nc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 7-(4-bromo-2-chlorophenyl)-6-(4-chloro-phenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine (303 mg, 0.63 mmol) and NEt3 (221 μL, 1.6 mmol) in 10 mL of CH2Cl2 was added 4-bromobutyryl chloride (110 μL, 0.95 mmol). After stirring at rt for 16 h, the reaction mixture was combined with saturated aq NaHCO3 (20 mL). The aq layer was separated and extracted with CH2Cl2 (3×20 mL). The organic layers were combined, dried over MgSO4, and concentrated to afford the product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=O)=[CH:4][C:3]=1[F:16].B.Cl>O1CCCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[F:16]
Reactant: CC(C)CCNC(=O)c1ccc(Br)c(F)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCNCc1ccc(Br)c(F)c1
Temperature: 25 °C

Procedure:
4-Bromo-3-fluoro-N-(3-methylbutyl)benzamide (I-5a: 2.6 g, 9.02 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with 1M borane in tetrahydrofuran (20 ml, 18.04 mmol) at room temperature. After heating at reflux for 24 hours, the reaction mixture was carefully treated with concentrated HCl and then heated at reflux for 1 additional hour. After cooling to ambient temperature, the reaction mixture was filtered and the resulting solid suspended in 1N aqueous NaOH and the mixture extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The resulting material used in the subsequent reaction without further purification.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[C:6]([O-])=[O:7].[Na+].C(Cl)(=O)C(Cl)=O.C[N:24](C=O)C>O>[C:6]([C:5]1[CH:9]=[C:10]([CH:11]=[C:3]([I:2])[CH:4]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])[NH2:24]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)cc(C(=O)[O-])c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(I)cc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
20 ml of 1 M hydrochloric acid were added to a solution of 3.88 g (11.8 mmol) of sodium 3-iodo-5-(methoxycarbonyl)benzoate [J. H. Ackermann et al., J. Med. Chem. 1966, 9 (1), 165-168] in 100 ml of water. After 10 min, the mixture was extracted three times with in each case about 100 ml of ethyl acetate. The combined organic extracts were washed with saturated sodium chloride solution and dried over anhydrous magnesium sulphate. After filtration, the solvent was removed on a rotary evaporator. The residue that remained was dissolved in 75 ml of dichloromethane, and 5.2 ml (59.1 mmol) of oxalyl chloride and a small drop of DMF were added at RT. After 1 h of stirring at RT, all volatile components were removed on a rotary evaporator. The residue was then dissolved in 50 ml of dioxane and, at a temperature of about 0° C., slowly added dropwise to 44 ml of a 25% strength aqueous ammonia solution. After the dropwise addition had ended, the cooling bath was removed and stirring was continued at RT for 30 min. The precipitated product was then filtered off with suction, washed with cold water and dried under high vacuum. This gave 3.02 g (81% of theory, 97% pure) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]=[C:20]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:21]P(=O)(OC)OC>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:21][C:20](=[O:19])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:11][C:10]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Reactant: CCCCCCC(=O)CP(=O)(OC)OC
Product: CCCCCCC(=O)C=Cc1ccc(OCc2ccccc2)c(OC)c1
Yield: 72.7 %

Procedure:
By following the procedure as in Reference Example 1(a) using 1.2 g of 4-benzyloxy-3-methoxybenzaldehyde and 1.53 g of dimethyl 2-oxooctylphosphonate, 1.27 g of 1-(4-benzyloxy-3-methoxyphenyl)-1-nonen-3-one was obtained. Melting point 78°-81° C.
Reaction SMILES: [CH3:1][C:2](Cl)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:17][Sb-:18]([F:23])([F:22])([F:21])([F:20])[F:19].[Na+]>CO>[F:17][Sb-:18]([F:23])([F:22])([F:21])([F:20])[F:19].[CH3:1][C:2]([N+:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccncc1
Reactant: CC(C)(Cl)c1ccccc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CO
Product: CC(C)(c1ccccc1)[n+]1ccccc1

Procedure:
4.644 g (0.03 mol) of α,α-dimethylbenzyl chloride and 2.373 g (0.03 mol) of pyridine were reacted in 40 ml of methanol at 40° C. for 3 days. After the reaction, the solvent was evaporated in vacuo and ether-water was added to the residue to extract unreacted reactants in the etherial layer. To the aqueous layer was added 7.7 g (0.03 mol) of sodium hexafluoroantimonate. The resulting crystals were suction filtered, washed and dried to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1>O>[Cl:9][C:4]1[N:3]=[C:2]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Clc1cc(I)cc(Cl)n1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 120 °C
Yield: 42.6 %

Procedure:
A mixture of 2,6-dichloro-4-iodopyridine (1 g, 3.65 mmol) and tert-butyl 3-aminopiperidine-1-carboxylate (3.66 g, 18 mmol) in a sealed tube was heated at 120° C. for 3 days. After cooling, the mixture was poured into 100 mL of water. The solid was collected by filtration and purified by flash chromatography on silica gel eluting with ethyl acetate to provide 680 mg of the title compound. Yield: 43%. MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C
Reactant: NC(=NO)C1CC1
Product: Cc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C

Procedure:
80 mg (0.21 mmol) of the compound from Example 132A and 32 mg (0.32 mmol) of N′-hydroxycyclopropanimidamide were reacted according to the General Method 2. Yield: 41 mg (45% of theory)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Si]([O:41][NH2:42])(C(C)(C)C)(C)C.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:42][OH:41])=[O:19])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccc(OCCCCC(=O)NO)cc2)cc1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
To a solution in THF (13 mL) of 5-(4-(4-cyanophenyl)phenoxy)pentanoic acid (0.50 g, 1.7 mmol), prepared as in step 1, was added DMF (10 μL, 0.13 mmol), and oxalyl chloride (0.16 mL, 1.9 mmol) and the reaction mixture was stirred for 2 hours. A solution in THF (2 mL) of O-tert-butyldimethylsilylhydroxylamine (0.30 g, 2.0 mmol) and triethylamine (0.25 mL, 1.8 mmol) was added dropwise via syringe and the reaction mixture was stirred for 3.5 hours. The reaction mixture was quenched with methanol and concentrated in vacuo. The residue was partitioned between aqueous 1M NaOH and ethyl ether, and the aqueous phase was extracted with ethyl ether. The aqueous phase was taken to pH 2 with concentrated HCl and extracted three times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give a white solid. Recrystallization from ethyl acetate gave 5-[4-(4-cyanophenyl)phenoxy]pentanohydroxamic acid (0.24 g) as a white solid. mp 141.8°-142.6° C. 1H NMR (DMSO-d6) δ 1.59-1.84 (c, 4H), 2.03 (t, 2H, J=7.5 Hz), 4.03 (t, 2H, J=6 Hz), 7.06 (d, 2H, J=9 Hz), 7.69 (s, 1H), 7.72 (s, 1H), 7.81-7.92 (c, 4H), 8.71 (s, 1H), 10.39 (s, 1H). IR (KBr) 3200, 3030, 3010, 2860, 2240, 1630, 1600, 1540, 1520, 1490, 1470, 1460, 1390, 1290, 1250, 1180, 1110, 980, 850, 820, 630, 580, 530 cm-1. MS (DCI/NH3) 294 (M-16), 311 (M+H)+, 328 (M+NH4)+. Anal. Calcd for C18H18N2O3 : C, 69.66; H, 5.85; N, 9.03. Found: C, 69.54; H, 5.73; N, 8.99.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([F:34])=[CH:29][CH:28]=3)[C:7]2[CH:22]=[CH:21][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.O1CCCC1.[OH-].[Na+].Cl>C(OCC)(=O)C.O.CO>[CH3:1][C:2]1([CH3:35])[CH2:5][CH:4]([CH:6]([NH:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([F:34])=[CH:29][CH:28]=3)[C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[CH:21][CH:22]=2)[CH2:3]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(Nc2cnc3ccc(F)cc3c2)C2CC(C)(C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CC(C(Nc2cnc3ccc(F)cc3c2)c2ccc(C(=O)NCCC(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99 %

Procedure:
To a flask containing ethyl 3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoate (7.4 mg, 0.0420 mmol) was added tetrahydrofuran (0.105 mL), methanol (0.105 mL), and 1 N sodium hydroxide (0.105 mL, 0.105 mmol). The reaction was stirred for 4.5 h at room temperature. The reaction was then diluted with ethyl acetate and water. 1 N hydrochloric acid (0.105 mL) was then added dropwise to bring the pH to 3. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to provide 3-(4-((3,3-dimethylcyclobutyl)(6-fluoroquinolin-3-ylamino)methyl)benzamido)propanoic acid
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[CH3:19][O:20][C:21]([C@:23]1([CH2:29]O)[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH3:19][O:20][C:21]([C@:23]1([CH2:29][O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])[CH2:27][CH2:26][CH2:25][N:24]1[CH3:28])=[O:22]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)[C@]1(CO)CCCN1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@]1(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (11.7 g, 38.1 mmol) was added to a solution of Intermediate 85e (2.20 g, 12.7 mmol) and Et3N (12.8 g, 127 mmol) in DCM (100 mL) at 0° C., then the mixture stirred at RT for 30 min. The mixture was diluted with DCM and washed with 10% aq. K2CO3 solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow solid (2.51 g, 65%). 1H NMR (400 MHz, CDCl3): 0.97-1.15 (2H, m), 1.72-1.96 (2H, m), 2.23-2.35 (2H, m), 2.46 (3H, s), 2.89-2.99 (2H, m), 3.69 (3H, m), 4.12-4.22 (2H, m).
Reaction SMILES: [C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.C([CH:12]=[C:13]([C:17]#[N:18])[C:14]([OH:16])=[O:15])C(C)C.[OH-].[K+]>O>[C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[C:17]([C:13](=[CH2:12])[C:14]([OH:16])=[O:15])#[N:18]
Reactant: CC(C)CC=C(C#N)C(=O)O
Agent: C1=C2CCC(=C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C#N)C(=O)O
Temperature: 25 °C

Procedure:
Into a flask fitted with a condenser and magnetic stirring bar is charged 12.3 g (0.05 mole) norbornadiene/isobutyl 2-cyanoacrylic acid adduct and a solution of 4.9 g 86% potassium hydroxide (0.075 mole) in 75 ml. of water. After heating at reflux for 1.5 hours, the solution is cooled to room temperature and extracted with 2 × 25 ml. of hexane to remove any nonsaponified adduct. The aqueous phase is acidified to pH 2 with 6 N hydrochloric acid and the liberated oily product is taken up in 100 ml. ethyl acetate. The extract is filtered to remove some white insoluble solids (0.9 g., m.p. 182° C.) and the filtrate washed with 3 × 26 ml. water, 1 × 25 ml. saturated sodium chloride solution, and solvent stripped in vacuo to a pale yellow, viscous oil (8.7 g.). Crystallization of the oily product from benzene/hexane in the cold affords 4.2 g of the norbornadiene/2-cyanoacrylic acid adduct, white crystals, m.p. 83°-86° C. Another 3.0 g. of adduct, m.p. 81°-84° C., is obtained on concentration of the mother liquors and cooling. The combined crops of adduct are recrystallized from 1:2 benzene/hexane to afford 5.9 g of pure adduct, white crystals, m.p. 81°-83° C. Anal: Neutralization Equivalent: Found, 189.06 g/equiv.; Calculated (Theory), 189.22 g/equiv.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([Cl:14])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:15]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][CH2:20][CH:17]3[CH2:18][CH2:19][O:15][CH2:16]3)[N:7]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Reactant: NCC1CCOC1
Product: Clc1cc(-c2ccnc(NCC3CCOC3)n2)ccn1

Procedure:
The title compound was prepared from 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) and tetrahydro-3-furanmethanamine (i.e., the product of Step C) in the same fashion as described in Example 9, Step A.
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:37][C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([C:48]([F:51])([F:50])[F:49])[CH:39]=2)[C:19]2[N:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]3[C:34](=[O:35])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:36])[N:23]=2)[C:13]2[CH:52]=[C:53]([CH3:60])[C:54]([C:56]([F:59])([F:58])[F:57])=[CH:55][C:12]1=2)C1C=CC=CC=1.[H][H]>CO.[Pd]>[F:51][C:48]([F:49])([F:50])[C:40]1[CH:39]=[C:38]([CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=1)[CH2:37][N:18]([C@H:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][CH2:9][OH:8])[C:12]2[CH:55]=[C:54]([C:56]([F:57])([F:58])[F:59])[C:53]([CH3:60])=[CH:52][C:13]1=2)[C:19]1[N:20]=[N:21][N:22]([CH2:24][CH2:25][N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[N:23]=1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(CCOCc1ccccc1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(CCO)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCN2C(=O)c3ccccc3C2=O)n1

Procedure:
To a solution of (S)-2-(2-{5-[[1-(2-Benzyloxy-ethyl)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl]-(3,5-bis-trifluoromethyl-benzyl)-amino]-tetrazol-2-yl}-ethyl)-isoindole-1,3-dione (Example 126, Step 3) (0.09 mmol) in methanol (20 mL), add a catalytic amount of 10% Pd/C after purging with nitrogen. Purge the reaction with a balloon of hydrogen and stir under a balloon of hydrogen for 14 h. Purge the reaction with nitrogen and filter through Celite®. Collect the filtrate and remove solvent under vacuum. Chromatograph the reaction over silica gel eluting with ethyl acetate/hexane (15-45%) to afford the title compound.