Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH:19]([CH3:21])[CH3:20].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([NH2:34])[CH:31]=[N:32][CH:33]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:34][C:30]3[CH:31]=[N:32][CH:33]=[C:28]([N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH:29]=3)=[C:3]([CH:19]([CH3:21])[CH3:20])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Solvent: Cc1ccccc1
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 4-chloro-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (45.0 mg, 0.150 mmol) and 5-morpholinopyridin-3-amine in toluene to give 7-fluoro-3-(1-methylethyl)-N-(5-(4-morpholinyl)-3-pyridinyl)-2-(2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, chloroform-d) δ ppm 8.69-8.76 (1H, m), 7.84-7.92 (2H, m), 7.71-7.83 (3H, m), 7.68 (1H, d, J=7.8 Hz), 7.39 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 7.18 (1H, ddd, J=9.2, 8.1, 2.6 Hz), 6.25 (1H, t, J=2.3 Hz), 6.03 (1H, s), 3.71-3.83 (4H, m), 3.33-3.43 (1H, m), 2.95-3.08 (4H, m), 1.32 (6H, d, J=7.2 Hz). Mass Spectrum (ESI) m/e=444.2 (M+1).
Reaction SMILES: [ClH:1].O[C:3]([CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[O:26])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)(C)C>[ClH:1].[C:4]1([C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH2:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[O:26])[CH2:20][CH2:21]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1cccs1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1cccs1
Temperature: 80 °C

Procedure:
A mixture of 22.8 g (0.05 mole) of 4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]-1-(2-thienyl)butan-1-one hydrochloride, 500 ml of isopropyl alcohol and 500 ml of concentrated HCl was heated on a steam bath for 3 hours, and the solvent was removed under vacuum. Isopropyl alcohol and 300 ml of water were added to the residue and heated to 80° C. Upon cooling a precipitate formed which was collected and recrystallized from methanol-ethyl acetate and toluene to give the desired product, M.P. 132.5°-134.5° C.
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15]>C1COCC1.[Zn]>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:15]
Reactant: N#Cc1ncccc1Br
Reactant: O=C(Cl)c1cccc(Br)c1
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ncccc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.3 %

Procedure:
A suspension of highly active zinc (Rieke zinc) in THF (100 mg/mL, 12.7 mL, 19.4 mmol) was added via a syringe to a solution of 3-bromo-2-cyanopyridine (1.189 g, 6.497 mmol) in anhydrous THF (20 mL) under an atmosphere of argon. The mixture was stirred for four h at room temperature and then at 50° C. for 15 min. The remaining zinc powder was allowed to settle at the bottom of the flask overnight at −20° C. The top solution was transferred to another flask and cooled to −20° C. To this was added a 1 M solution of copper cyanide di(lithium bromide) complex in THF (6.82 mL) and the resulting mixture was stirred for 5 min at −20° C. and for 35 min at 0° C. and then cooled to −30° C. prior to the addition of 3-bromobenzoyl chloride (1.78 g, 8.12 mmol). The mixture was stirred for 6 h during which time the temperature went from −30° C. to 0° C. The reaction was quenched by the addition of saturated ammonium chloride solution and ethyl acetate was added. The phases were separated and the organic phase was washed with 1 M sodium carbonate solution and with brine. The solution was dried over magnesium sulfate and evaporated. Purification by column chromatography using a gradient of increasing concentration of ethyl acetate in heptane (0-50%) gave 1.18 g (63% yield) of the title compound. 1H NMR (CDCl3) δ 8.92 (dd, 1H), 7.98 (dd, 1H), 7.96 (t, 1H), 7.84-7.81 (m, 1H), 7.73-7.70 (m, 1H), 7.68 (dd, 1H), 7.43 (t, 1H); MS (CI) m/z M+ 287, 289.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:16][CH:15]=1.[OH-].[Na+]>O1CCOCC1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[C:5]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:18][CH:19]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(OC)cc1OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)c(OCc2ccc(OCCc3nc(-c4ccccc4)oc3C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title D compound, 4-methoxy-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}-benzoic acid methyl ester (220 mg, 0.46 mmol) is taken up in 5 mL of 1,4-dioxane and 1.4 mL of 1 N aqueous NaOH is added. The solution is stirred overnight at RT, followed by 5 h at 90° C. The mixture is concentrated under vacuum, and the residue is acidified (4 N HCl) and extracted with EtOAc. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated to give 4-methoxy-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyloxy}benzoic acid: m.p. 113-115° C.; ESI-MS 460 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]1[NH:33][C:32](=[O:34])[CH2:31][CH2:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:33]3[CH:29]([CH3:28])[CH2:30][CH2:31][C:32]3=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: CC1CCC(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 43.9 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (903 mg) described in Preparation Example 110 and 5-methylpyrrolidin-2-one (198 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (412 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH3:17][O:16][C:14]([C:12]1[CH2:13][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH:11]=1)=[O:15]
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C1=CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product from Step A (9.8 g, 40.6 mmol) and DBU (9 mL, 60 mmol) in DCM (70 mL) was stirred at rt overnight. The mixture was cooled to 0° C. and washed with 1N HCl aqueous solution and brine, dried over Na2SO4. Evaporation and purification by column chromatography (eluent: 20% EtOAc in hexanes to 40%) gave the product as a white solid. 1H-NMR (400 MHz, CDCl3): δ 1.44 (s, 9H), 2.36-2.47 (m, 2H), 2.88-2.99 (m, 2H), 3.74 (s, 3H), 4.36 (br s, 1H), 4.71 (br s, 1H), 6.71-6.72 (m, 1H). LC/MS: C12H19NO4: m/z 264.0 (M+Na).
Reaction SMILES: C(OC1N=C2C(NC=N2)=C(N)N=1)CCCCCCC.[C:20]([NH:28][C:29]1[C:30]2[N:31]=[CH:32][N:33]([C:45]=2[N:46]=[C:47](C)[N:48]=1)[C@@H:34]1[O:41][C@H:38]([CH2:39][OH:40])[C@@H:36]([OH:37])[C:35]1=S(=O)=O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C.C(N)(=O)CCCCCCC>CN(C=O)C>[C:20]([NH:28][C:29]1[C:30]2[N:31]=[CH:32][N:33]([C:45]=2[N:46]=[CH:47][N:48]=1)[C@@H:34]1[O:41][C@H:38]([CH2:39][OH:40])[C@@H:36]([OH:37])[CH2:35]1)(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(NC(=O)c2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)C3=S(=O)=O)c2n1
Agent: CCCCCCCC(N)=O
Agent: CCCCCCCCOc1nc(N)c2[nH]cnc2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1

Procedure:
Synthesis of 5LO sequence 5′-GAA GTC ACT GGA ACG-3′ (SEQ ID NO:21) containing 2-octanoxyadenine at specific positions is described. A solution of N6-benzoyl-2′-deoxy-2-methyl-sulfonyladenosine, ethyl diisopropylamine, octanoylamine, and DMF is heated to 100° C. for 30 min and evaporated to dryness under reduced pressure. Recrystallization of the residue affords N6-benzoyl-2′-deoxyadenosine with the carbon chain in the 2-position. This material is converted by procedures of examples 107 and 108 above into its 5′-DMT-3′-β-cyanoethyldiisopropylphosphoramidite derivative which is inserted into the 5LO-sequence 5′-GAA GTC ACT GGA ACG (SEQ ID NO:21) via automated, solid phase DNA synthesis.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[Br:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:4]2[CH2:5][C@H:3]2[NH:2][CH2:27][C:26]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:7][CH:8]=1)=[O:21]
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Br)c2)cc1
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: COc1ccc(CN[C@@H]2C[C@H]2c2ccc(NC(=O)c3cccc(Br)c3)cc2)cc1OC
Temperature: 70 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-bromobenzamide hydrochloride (80 mg) in methanol (2 mL) were added 3,4-dimethoxybenzaldehyde (36.2 mg) and sodium hydrogen carbonate (27.4 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (12.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate) to give the title compound (44.2 mg).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:40])[CH2:20][CH2:21][CH2:22][N:23]2[CH2:39][CH2:38][C@@H:26]3[N:27]4[C:36]5[C:35]([C@@H:25]3[CH2:24]2)=[CH:34][CH:33]=[CH:32][C:31]=5[N:30]([CH3:37])[CH2:29][CH2:28]4)=[CH:15][CH:14]=1.[BH4-].[Na+]>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][CH2:21][CH2:22][N:23]2[CH2:39][CH2:38][C@@H:26]3[N:27]4[C:36]5[C:35]([C@@H:25]3[CH2:24]2)=[CH:34][CH:33]=[CH:32][C:31]=5[N:30]([CH3:37])[CH2:29][CH2:28]4)=[CH:15][CH:14]=1
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(O)c3ccc(F)cc3)CC[C@@H]12
Temperature: -10 °C
Yield: 99.8 %

Procedure:
1-(4-Fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-one tosylate salt (8.58 g, 15.2 mmol) is dissolved in 150 mL of methanol. The obtained brown solution is cooled to −10° C., and then NaBH4 (1.72 g, 45.5 mmol) is added slowly. After the addition is complete, the reaction mixture is stirred at room temperature for an hour, and then quenched by adding 20 mL of water. After solvent is removed by rotary evaporation, the residue is treated with 50 mL of 1N NaOH aqueous solution, and then extracted with methylene chloride four times. The combined organic phase is washed with water, dried with anhydrous sodium sulfate, and then evaporated to dryness under vacuum to give 6 g of white foamy solids with 97.8% purity and 99% yield. MS (ESI) m/z 396.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[OH:22])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO.[Fe]>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:8]([CH2:20][C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[OH:22])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CCN(Cc2ccccc2)C[C@H](O)c2ccccc2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(CCN(Cc2ccccc2)C[C@H](O)c2ccccc2)cc1
Yield: 92.8 %

Procedure:
To a solution of 13.4 g of (R)-2-[N-benzyl-N-[2-(4-nitrophenyl)ethyl]amino]-1-phenylethanol in 150 ml of methanol were added 8.6 g of iron powder and 40 ml of a 2N aqueous hydrochloric acid solution. The reaction mixture was heated to reflux for two hours, a 1N aqueous solution of sodium hydroxide was added thereto, and the insoluble matters thus produced were filtered off using Celite. The filtrate was concentrated in vacuo to remove the methanol. The resulting aqueous phase was extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to give 11.45 g of (R)-2-[N-[2-(4-amino-phenyl)ethyl]-N-benzylamino]-1-phenylethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]2[C:6]([O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]2=[O:17])=[CH:5][CH:4]=1.[NH2:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[N:21]1([CH2:20][CH2:19][NH:18][C:12]2[C:13]3[C:14](=[O:17])[C:15]4[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:16]=4)[O:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCN1CCCC1
Reactant: COc1ccc2oc3ccccc3c(=O)c2c1
Solvent: c1ccncc1
Product: COc1ccc2oc3cccc(NCCN4CCCC4)c3c(=O)c2c1
Yield: 80.4 %

Procedure:
A mixture of 1-chloro and 3-chloro isomers of 7-methoxyxanthone (32.6 g, 0.125 mole) of N-(2-aminoethyl)pyrrolidine (19.43 g, 0.17 mole) were refluxed in 150 mL of pyridine for 24 h with exclusion of moisture. The pyridine and excess of diamine was removed by vacuum distillation (ca. 12 mmHg, bath temp. 60°-72° C.), The distillation residue was dissolved in 200 mL of acetic acid, poured in 1.7 L water filtered and basified with NaOH pellets. The yellow-orange precipitate was filtered, washed with water an dried to give 34 g solid, which was chromatographed on silica gel. The first fraction was eluted with CHCl3. It was a mixture of starting chloroisomers and some minor by-products (18.5 g=56.7% melting range 135°-145° C. The desired compound was eluted with CHCl3 /EtOH (80:20) (13 g=30.7%), mp-93°-94° C. The analytical sample was recrystallized from ethanol, mp= 92°-93° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:33]5[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. 2-Methoxypyridin-3-ylboronic acid (59.6 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 34.7 mg, 0.0300 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The crude product was evaporated to dryness, dissolved in 1 mL of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 439.1. found 440.1 (M+1)+. Retention time 1.94 minutes.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]([C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=1)[CH2:5][C:6]1[CH:23]=[CH:22][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11])=[CH:8][CH:7]=1.Cl.[C:42]1([NH:48]N)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>[Cl-].[Cl-].[Zn+2].C(O)(=O)C>[NH:48]1[C:42]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:3]([CH:4]([C:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:11])=[CH:22][CH:23]=2)=[CH:2]1
Reactant: NNc1ccccc1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(CC(CC=O)c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=C(O)CCNC(=O)c1ccc(CC(c2cccc(-c3ccc(OC(F)(F)F)cc3)c2)c2c[nH]c3ccccc23)cc1
Temperature: 80 °C

Procedure:
A glacial acetic acid solution (4 mL) containing the intermediate from Step C (150 mg, 0.27 mmol), phenyl hydrazine hydrochloride (51 mg, 0.35 mmol) and ZnCl2 (110 mg, 0.81 mmol) was heated at 80° C. for 1 hour. The solution was concentrated and partitioned between aqueous 1N HCl and ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by RP-HPLC and the isolated material was resolved using chiral OJ SFC-HPLC to give the title compounds. Isomer A: Chiral LC1 4.85 min, LCMS1 3.80 min. (M+H)=572. Isomer B: Chiral LC1 12.09 min, LCMS1 3.80 min. (M+H)=572. Representative 1H NMR (400 MHz, CD3OD): δ 7.58 (d, J=8.2 Hz, 2H); 7.47 (d, J=8.6 Hz, 2H); 7.37-7.14 (m, 11H); 7.01 (t, J=7.5 Hz, 1H); 6.85 (t, J=7.5 Hz, 1H); 4.57 (t, J=7.9 Hz, 1H); 3.63 (dd, J=6.7, 13.4 Hz, 1H); 3.56 (t, J=6.9 Hz, 2H); 3.36 (dd, J=9.1, 13.3 Hz, 1H); 2.57 (t, J=7.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH2:27]([NH:34][CH2:35][CH2:36][OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]([CH2:35][CH2:36][OH:37])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:14]=2)=[O:26])=[C:2]([Cl:1])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: OCCNCc1ccccc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N(CCO)Cc2ccccc2)cc1Cl

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-(benzylamino)ethanol via Procedure G. The crude product was purified on reverse phase HPLC to yield N4-benzyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxyethyl)terephthalamide. MS (Q1) 520 (M)+.
Reaction SMILES: Cl.[C:2]([O:8][C:9]1[CH:47]=[CH:46][C:12]([C:13]([O:15][C:16]2[CH:17]=[C:18]([C:38](=[O:45])[CH2:39][NH:40][CH:41]3[CH2:44][CH2:43][CH2:42]3)[CH:19]=[C:20]([O:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=3)[CH:21]=2)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[S:48](=O)(=[O:51])([OH:50])[OH:49]>C(O)C.[Pd]>[S:48]([O:45][CH:38]([C:18]1[CH:19]=[C:20]([O:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=2)[CH:21]=[C:16]([O:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([O:8][C:2](=[O:7])[C:3]([CH3:4])([CH3:5])[CH3:6])=[CH:47][CH:46]=2)[CH:17]=1)[CH2:39][NH:40][CH:41]1[CH2:44][CH2:43][CH2:42]1)([OH:51])(=[O:50])=[O:49]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(=O)CNC3CCC3)c2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)Oc2cc(OC(=O)c3ccc(OC(=O)C(C)(C)C)cc3)cc(C(CNC3CCC3)OS(=O)(=O)O)c2)cc1

Procedure:
A solution of 2.2 g of 3',5'-bis-(4-pivaloyloxybenzoyloxy)-2-cyclobutylamino acetophenone hydrochloride in 75 ml of ethanol was hydrogenated at 380 kPa (55 psig) and 45° C. for 18 hrs in the presence of 0.4 g 10% Pd/C. After filtering off the catalyst the filtrate was evaporated to dryness to give an oil as residue. This oil was partitioned between ethyl ether and 10% sodium carbonate solution. The ether phase was dried over MgSO4, filtered and evaporated to dryness to give a crystalline residue. The residue was dissolved in ethanol which was acidified with ethanolic sulphuric acid to pH 5.5. After evaporation, the residue was recrystallized from isopropanol/ethyl ether. The identity of the product was confirmed with NMR.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:27])=[O:26])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][S:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:26])=[O:27])=[O:19]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NS(=O)(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of tert-butyl ({2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}sulfamoyl)carbamate 79 (0.35 g, 0.67 mmol) and Pd/C (10%, 0.12 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 80 (0.25 g, 88%) as a white foam.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[N+:15]([O-])=O)=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:15][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:7]=1[O:6][C:5]1[CH:18]=[CH:19][C:2]([OH:1])=[CH:3][CH:4]=1)[C:11]#[N:12]
Reactant: [H][H]
Reactant: N#Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(Oc2ccc(O)cc2)c(N)c1
Yield: 99 %

Procedure:
The product of Example 152A (500 mg, 1.952 mmol) was hydrogenated in methanol (20 mL) with hydrogen (1 atmosphere, balloon) and 10% palladium on carbon (50 mg) for 30 minutes. The reaction was vacuum filtered through a 0.45□ PTFE membrane and the catalyst washed with methanol. The filtrate was concentrated by rotary evaporation under vacuum to provide the title compound as a pinkish-beige solid (437 mg, 99%).