Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[C:19]1([CH2:25][C:26](OC)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1.CCOCC>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][CH:6]([C:3](=[O:5])[CH2:4][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
To a suspension of 60% sodium hydride (1.07 g) in THF (15 mL) at 0° C. was added a solution of 4-acetyl-1-(t-butoxycarbonyl)-piperidine from Step B2 (3.03 g, 13.3 mmol) and methyl phenylacetate (6.01 g, 39.9 mmol) in THF (6 mL) over 20 min. The reaction was stirred for another 4 h as it was allowed to warm to rt. The mixture was diluted with ether (30 mL) and poured into 1N HCl. The layers were separated and the aqueous layer was extracted three times with ether. The combined organic layers were washed with brine (150 ML), dried over sodium sulfate and concentrated. The crude product was purified by FC (20% ethyl acetate in hexanes) to give the title compound (3.02 g). Rf: 0.30 (20% ethyl acetate in hexane). Its NMR was the same as that obtained from the product of Method A above.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:15]2=[N:16][C:17]([NH:20][C:50]([CH:47]3[CH2:49][CH2:48]3)=[O:51])=[CH:18][CH:19]=[C:14]2[N:13]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(n1)c(-c1ccc3ccccc3c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CC1

Procedure:
20 mg of 3-(naphthalen-2-yl)-1-trityl-1H-pyrazolo[4,3-b]pyridin-5-ylamine was dissolved in 3 mL of toluene, and added with 20 μl of triethylamine and 10 μl of cyclopropanecarbonyl chloride at room temperature and stirred all day and night. The reaction solution was added with saturated aqueous sodium hydrogen carbonate, extracted with sodium acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), to afford 20 mg of the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](O)=[CH:9][CH:10]=1.[O:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1.C([Sn](CCCC)(CCCC)[C:43]1[CH:48]=[N:47][CH:46]=[CH:45][N:44]=1)CCC>>[O:23]1[CH2:28][CH:27]=[C:26]([C:16]2[CH:15]=[C:14]([F:20])[C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([C:43]5[CH:48]=[N:47][CH:46]=[CH:45][N:44]=5)=[CH:9][CH:10]=4)[C@@:5]4([CH2:4][O:3][C:2]([NH2:1])=[N:22]4)[C:18]=3[CH:17]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Product: NC1=N[C@@]2(CO1)c1cc(-c3cnccn3)ccc1Oc1c(F)cc(C3=CCOCC3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA22 above, but using (S)-2-amino-2′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (prepared as described in Method BB40 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-(tributylstannyl)pyrazine
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.CCOC(C)=O>CO.CCCCCC>[Cl:1][C:2]1[C:3]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(Oc2ccc3c(c2)COB3O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1cnc(Oc2ccc3c(c2)COB3O)c(Cl)c1
Yield: 92.2 %

Procedure:
Hydrolysis of ethyl 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (0.9 g, 2.7 mmol) with 1N NaOH (11 mL) in MeOH (50 mL) overnight at r.t. followed by acidification with 6N HCl, work-up and recrystallization from EtOAc and hexane afforded off-white solid of the title carboxylic acid compound (0.76 g, 2.49 mmol, yield 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[CH:6]C=1.[C:9](=[O:12])([O-])[O-].[Ca+2].[Cl:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]>CN(C)C=O>[ClH:14].[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][N:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:9]=1[OH:12])[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)=CCCl
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CC(C)=CCN(CC=C(C)C)c1ccccc1O
Product: Cl
Temperature: 65 °C

Procedure:
To a two-liter four-necked round-bottomed flask equipped with a nitrogen inlet, temperature probe, mechanical stirrer and a 500 mL pressure equalizing dropping funnel with an attached condenser, was added 350 mL of N,N-dimethylformamide (DMF), m-aminophenol (109.1 gm, 1.0 mole) and calcium carbonate (50 gm, 0.5 mole). The mixture was heated with a heating mantle to 65° C. and the addition funnel was charged with 1-chloro-3-methyl-2-butene (214 gm, 2.05 mole). The 1-chloro-3-methyl-2-butene was added over 15 minutes with vigorous stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([OH:17])=O)=[CH:12][N:11]=[C:10]1[S:18][CH2:19][CH2:20][CH3:21].OC1CC(=O)NC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:46][O:47][C:48](=[O:58])[C@H:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH2:50].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH3:46][O:47][C:48](=[O:58])[C@H:49]([CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[NH:50][C:15]([CH2:14][C:13]1[N:9]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]([S:18][CH2:19][CH2:20][CH3:21])=[N:11][CH:12]=1)=[O:17]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CC(O)C(=O)N1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCSc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.6 %

Procedure:
A solution of 2-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl]acetic acid (0.52 g, 1.6 mmol) in tetrahydrofuran (20 mL) was stirred with N hydroxysuccinimide (0.203 g, 1.76 mmol) and dicyclohexylcarbodiimide (0.33 g, 0.16 mmol) for 30 minutes. Then L-phenylalanine methyl ester hydrochloride (0.449 g, 2.08 mmol) and triethylamine (0.21 g, 2.08 mmol) were added and the suspension was stirred at ambient temperature for 18 hours. The mixture was diluted with ethyl acetate, filtered and the concentrated filtrate was flash chromatographed over silica gel with 3:2 ethyl acetate/hexane to give 0.58 g (74%) of N-[{1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([I:14])[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[F:1][C:2]1[CH:18]=[C:17]([CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([I:14])[S:13][C:6]=12)[NH2:19]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Yield: 99.6 %

Procedure:
To a solution of 399 (2 g, 4.81 mmol) and NH4Cl (220 mg, 4.08 mmol) in 2:1 EtOH/water (75 mL) was added iron powder (2.28 g, 40.8 mmol) and the suspension was heated to reflux for 1 hour. The reaction mixture was filtered through celite and concentrated to afford 410 (1.85 g, 100% yield), that was used without further purification MS. (m/z): (M+1) 386.8 (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[C:7]2[CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.P(Cl)(Cl)([Cl:52])=O>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6]3=[C:7]([CH2:13][CH2:14][O:16][C:5]3=[CH:4][CH:3]=1)[CH:8]=[C:9]([Cl:52])[N:10]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(CCO)c2c(O)ccc(Br)c2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1cc2c3c(ccc(Br)c3n1)OCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a stirred solution of 8-bromo-5-hydroxy-4-(2-hydroxyethyl)quinolin-2(1H)-one (0.560 g; 1.971 mmol) in tetrahydrofuran (25 ml) was added triphenylphosphine (0.775 g; 2.96 mmol) followed by the dropwise addition of diisopropyl azodicarboxylate (0.582 ml; 2.96 mmol). The reaction mixture was stirred at room temperature for 2 h, concentrated under reduced pressure and the remaining crude residue was slowly added to phosphorus oxychloride (2.5 ml; 26.7 mmol) at room temperature. The reaction mixture was heated at 100° C. for 1 h and then cooled to room temperature before removing of the volatiles under reduced pressure. The residue was dissolved in dichloromethane, washed with a solution of sodium hydroxide 1N, water and brine, dried over magnesium sulphate and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.220 g (39%) of 7-bromo-5-chloro-2,3-dihydropyrano[4,3,2-de]quinoline as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[Cl:13][C:14]1[C:15]([CH:25]([CH3:27])[CH3:26])=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH:22]=1)[C:19](O)=[O:20]>>[ClH:13].[CH3:12][N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:19](=[O:20])[C:18]2[CH:22]=[C:14]([Cl:13])[C:15]([CH:25]([CH3:26])[CH3:27])=[CH:16][C:17]=2[O:23][CH3:24])[CH2:7]1
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1cc(C(C)C)c(Cl)cc1C(=O)O
Product: COc1cc(C(C)C)c(Cl)cc1C(=O)Nc1cccc2c1CCN(C)C2
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to Example 1 from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-chloro-4-iso-propyl-2-methoxybenzoic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:32][C:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([SH:47])=[CH:43][CH:42]=1)([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC#N>[CH3:39][C:33]([O:40][C:41]1[CH:42]=[CH:43][C:44]([S:47][CH2:2][C:3]2[S:7][C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[N:5][C:4]=2[CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:45][CH:46]=1)([CH3:32])[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S)cc1
Reactant: FC(F)(F)c1ccc(-c2nc(COC3CCCCO3)c(CCl)s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 250 ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added 5-(chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (7.87 g, 20.09 mmoles, 1 eq) and dry CH3CN (100 ml, 0.27M). Solid cesium carbonate (16.4 g, 50.22 mmoles, 2.5 eq) was added all at once followed by the quick addition of ethyl 2-methyl-2-(4-sulfanylphenoxy)propanoate (5.79 g, 24.11 mmoles, 1.2 eq) in dry CH3CN (10 ml). The reaction was allowed to stir at room temperature for 2 hours at which point the solvent was removed under reduced pressure. The resulting residue was partitioned between EtOAc and 1N NaOH. After the phases were separated the organic fraction was washed with H2O, brine and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield the titled compound in >100% yield. Sometimes because of the difficult separation between the thiophenol and the product, the crude product was carried forward without purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][NH:29][N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[Li][Li].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CC(C)=O>[CH2:1]([C:3]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:27]=[N:28][N:29]([C:49]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[N:30]=3)=[CH:16][CH:15]=2)=[C:11]([C:31]([OH:33])=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Agent: [Li][Li]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2c(C(=O)O)c1Oc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1

Procedure:
A mixture of the title compound of Example 2, 2-ethyl-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-oxy]-4-quinolinecarboxylic acid, dilithium salt (700 mg, 1.6 mmol), triethyl amine (245 microliters, 1.76 mmol), triphenylmethyl chloride (468 mg, 1.68 mmol) and acetone (8 mL) was stirred at room temperature for 36 hours. The mixture was concentrated in vacuo to yield the crude product as a waxy solid (1.35 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH:13]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)=[CH:11][CH:10]=3)=[O:16])[CH2:15][CH2:14]1
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (39 mg, 0.200 mmol) to afford the desired product (17 mg, 36%) as an off-white solid: ESI MS m/z 476 [C27H33N5O3+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:19]([CH3:28])[C:18]([CH:29]2[O:34][CH2:33][CH2:32][NH:31][CH2:30]2)=[N:17]1.[C:35]1(=O)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]2[N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[Cl:9])[N:17]=[C:18]([CH:29]3[O:34][CH2:33][CH2:32][N:31]([CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)[CH2:30]3)[C:19]=2[CH3:28])=[CH:26][CH:25]=1
Reactant: Cc1c(C2CNCCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1c(C2CN(C3CCCCC3)CCO2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Triethyl amine (37 μl, 0.27 mmol) was added into the solution of 2-[1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazol-3-yl]-morpholine hydrochloride 5A-2 (75 mg, 0.18 mmol) and cyclohexanone (18 μl, 0.18 mmol) in 0.5 ml 1,2-dichloroethane. The reaction mixture was then treated with sodium triacetoxyborohydride (52 mg, 0.25 mmol) followed by acetic acid at room temperature. Upon the completion of the reaction, the reaction mixture was partitioned with ethyl acetate and saturated NaHCO3. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (silica, 60% ethyl acetate/hexanes) to give the title compound 5A-3 as a white solid (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:39]2[CH:44]=[CH:43][C:42]([O:45][C:46](=[O:48])[CH3:47])=[CH:41][CH:40]=2)[C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](Cl)=[O:33])=[CH:25][CH:24]=1)(=[O:21])[CH3:20].O>C(Cl)Cl>[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:39]2[CH:40]=[CH:41][C:42]([O:45][C:46](=[O:48])[CH3:47])=[CH:43][CH:44]=2)[C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:33])=[CH:27][CH:28]=1)(=[O:21])[CH3:20]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CC(=O)Oc1ccc(C(c2ccc(OC(C)=O)cc2)c2ccccc2C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccccc2C(c2ccc(OC(C)=O)cc2)c2ccc(OC(C)=O)cc2)c(OC)c1
Reaction time: 7 h

Procedure:
In 20 ml of methylene chloride were dissolved 1.08 g of 2,4-dimethoxyaniline and 4.5 ml of triethylamine. To this solution was dropwise added under ice cooling 20 ml of methylene chloride containing 3 g of 2-[bis(4-acetoxyphenyl)methyl]benzoyl chloride obtained in Reference Example 2. After stirring for 7 hours, water was added thereto. The organic layer was separated off, and the aqueous layer was extracted with chloroform. The chloroform layer was combined with the organic layer, and the combined organic layer was washed with 2N aqueous hydrochloric acid solution and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure to give 2.6 g of the desired product (Compound 2) as an oily matter.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23].[O:24]([CH2:31][CH2:32][NH2:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[O:24]([CH2:31][CH2:32][NH:33][CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[N:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]1[CH3:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CO)C1C
Reactant: NCCOc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=O)C(=CNCCOc2ccccc2)C1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.6 g. of 3-hydroxymethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid, ethyl ester and 685 mg. of phenoxyethylamine in 15 ml. of benzene is allowed to stir overnight at room temperature. The reaction mixture is concentrated to an oil and partitioned between 50 ml. of chloroform and 50 ml. of 1N aqueous sodium hydroxide. The chloroform layer is separated, dried over magnesium sulfate and concentrated to give 1.9 g. of the desired product as a foam.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:26][C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:28])[C:5](=[O:25])[NH:6][C@H:7]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:17])=[O:16])[CH2:9][CH:8]1[OH:24].C(N(CC)CC)C>CS(C)=O.O>[CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:26][C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:28])[C:5](=[O:25])[NH:6][C@H:7]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:17])=[O:16])[CH2:9][C:8]1=[O:24]
Reactant: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was added to a solution of quinoline-6-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide (130 mg, 0.235 mmol) in DMSO (2.0 ml) and triethylamine (0.2 ml, 1.4 mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore, additional triethyl amine (0.2 ml, 1.4 mmol) and sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was added and the reaction was stirred an additional hour. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (3% MeOH/CH2Cl2) gave the title compound (100 mg, 77%): 1H NMR:9.0 (sm 1H), 8.70 (s, 1H), 7.90-8.30 (m, 6H), 7.50-7.55 (m, 2H), 7.10 (d, 1H), 7.0 (d, 1H), 5.10-5.15 (m, 1H), 4.70-4.80 (m, 2H), 4.35-4.40 (m, 1H), 3.85 (d, 1H), 2.0-2.25 (m, 3H), 1.70-1.80 (m, 2H), 1.60-1.70 (m, 2H), 0.90-1.10 (m, 9H); Electrospray mass spec: M+H+=552.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH2:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(O)(=O)C.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([NH:26][CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])([CH3:24])[CH3:25])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: C=CC(=O)OC
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C(C)(C)N)cc3)n2)cc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCNC(C)(C)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Cl)c3)no2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl) phenyl)propan-2-amine, acetic acid (132 mg, 0.306 mmol) was added to a 5 mL microwave vial equipped with a stirring bar. Methyl acrylate (52.6 mg, 0.611 mmol), and MeOH (3.0 mL) were added, the vial capped, and the reaction heated to 120° C. for 90 min under microwave irradiation (Biotage Optimizer, 300 W). After 90 min another aliquot of methyl acrylate (52.6 mg, 0.611 mmol) was added and the reaction submitted for another 60 min at 120° C. Reaction was cooled and the solvent removed under reduced pressure. Crude material was purified by RP-HPLC (A=50 mM ammonium acetate, B=acetonitrile; 30-70% B over 30.0 min (21.0 mL/min flow rate); 21.2×250 mm Thermo Hyperprep C18 column, 8 μm particles) to give methyl 3-(2-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)propan-2-ylamino)propanoate (83.5 mg; 59.7%). LCMS (Table 1, Method f) Rt=2.78 min, m/z=458.29 (M+H)+,