Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[CH2:14]([NH2:16])[CH3:15]>C(Cl)Cl>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[CH3:1])[C:6]([NH:16][CH2:14][CH3:15])=[O:7]
Reactant: CCN
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCNC(=O)c1ccc(C)c(N)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-methyl-3-nitro-benzoyl chloride (1.0 g, 5.0 mmol) was dissolved in DCM, and the solution was cooled to 0° C. Ethyl amine (2.0 M in THF, 5.0 mL, 10 mmol) was added dropwise to the acid chloride, and the reaction stirred at 0° C. for 5 min. The ice bath was removed and reaction continued to stir for 3. The solution was washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting aniline (0.75 g) was used without further purification.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[F:4][C:5]([F:12])([F:11])[C:6](=O)[CH2:7][C:8]#[N:9].Cl>CCO>[CH3:1][N:2]1[C:8]([NH2:9])=[CH:7][C:6]([C:5]([F:12])([F:11])[F:4])=[N:3]1
Reactant: CNN
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cn1nc(C(F)(F)F)cc1N
Yield: 20.9 %

Procedure:
A solution of methylhydrazine (5.0 g, 60 mmol) and 4,4,4-trifluoro-3-oxo-butyronitrile (9.8 g, 71 mmol) in EtOH (50 mL) was treated with conc. HCl (5 mL) and the resultant mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude product was dissolved in EtOAc washed with saturated aq. Na2CO3 solution until the washings were pH 8. The organics were concentrated and purified by pre-HPLC to provide 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (2.07 g, 21% yield). 1HNMR (300 MHz, DMSO-d6), δ 5.57 (s, 1 H), 5.54 (br s, 2 H), 3.55 (s, 3 H); MS (ESI) m/z: 166.1 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:20][CH:19]3[N:21]([CH3:22])[CH:16]([CH2:17][CH2:18]3)[CH2:15]2)=[CH:9][CH:8]=1)(=O)=O.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:22][N:21]1[CH:19]2[CH2:18][CH2:17][CH:16]1[CH2:15][CH:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8][CH:9]=1)[CH2:20]2
Reactant: CN1C2CCC1CC(Sc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C2
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C2CCC1CC(Sc1ccc(-c3ccccc3)cc1)C2
Temperature: 90 °C

Procedure:
To a mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl trifluoromethanesulfonate (0.4 g) and phenylboronic acid (0.25 g) in DMF (5 ml) were added triethylamine (0.58 ml) followed by dichlorobis(triphenylphosphine) palladium (II) (0.04 g). The solution was heated at 90° C. for 4 hours, cooled to room temperature and diluted with ethyl acetate. This was washed with saturated aqueous sodium hydrogen carbonate solution, then brine, dried (MgSO4), filtered and evaporated. Partial clean up was achieved using preparative LC-MS. The mixture was stirred with aqueous sodium hydroxide solution (0.5M) to hydrolyse residual triflate to the phenol. The product was extracted into ethyl acetate, still however contaminated with some of the phenol. The material was loaded onto a PE-AX column and eluted with methanol with the final clean up by preparative LC-MS to yield [1,1 ′-biphenyl]4-yl 8-methyl-8-azabicyclo[3.2. 1]oct-3-yl sulfide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@@H:15]([CH3:25])[CH2:16][NH:17][C:18](=O)OC(C)(C)C)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.CO.C(Cl)Cl>C(#N)C>[CH3:25][C@@H:15]1[N:14]2[C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]=[CH:5][C:4]=3[N:1]=[C:18]2[NH:17][CH2:16]1
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Solvent: ClCCl
Solvent: CO
Solvent: CC#N
Product: C[C@H]1CNc2nc3cnc4ccccc4c3n21

Procedure:
The title compound was prepared from tert-butyl (2S)-2-[(3-nitroquinolin-4-yl)amino]propylcarbamate according to the methods of Parts C through G of Example 22 with the following modifications. Part C was carried out in acetonitrile as the solvent. Part D required chromatography (SiO2, 0-6% methanol/CH2Cl2). Following chromatographic purification (SiO2, 20-40% CMA/CHCl3) in Part G, the title compound, (10S)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline (2.14 g), was obtained as an off white foam.
Reaction SMILES: B.CSC.[CH3:5][CH:6]([NH:13][C:14](=O)[CH3:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C1COCC1>[CH2:14]([NH:13][CH:6]([CH3:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:15]
Reactant: CCCCCCC(C)NC(C)=O
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCCCC(C)NCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
A 2M THF solution of borane-dimethylsulfide (31.5 mL, 63 mmol) was added dropwise to an ice water-cooled solution of N-(1-methylhept-1-yl)acetamide (5.13 g, 30 mmol) in THF (60 mL). The resulting solution was stirred at RT for 1 h, then was refluxed overnight. With ice-water cooling, the excess borane-dimethylsulfide was quenched by the dropwise addition of methanol (10 mL), and the mixture was allowed to stand at RT overnight. The amine hydrochloride could not be precipitated with the addition of HCl gas, so the amine hydrochloride was extracted into dilute HCl. The acidic aq solution was extracted with ether, then made basic and extracted with ethyl acetate. The ethyl acetate solution was dried (MgSO4) and concentrated to afford 3.70 g of impure N-ethyl-N-(1-methylhept-1-yl)amine as an amber oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([NH:14][C:15]2[C:16](=[O:34])[N:17]([C:21]3[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:24]([NH:26][CH:27]3[CH2:29][CH2:28]3)=[O:25])[CH:18]=[CH:19][N:20]=2)[CH2:13][CH2:12]1.[CH2:35]([NH2:37])[CH3:36]>C(O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]4([C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3][CH2:2][NH:37][CH2:35][CH3:36])[CH2:13][CH2:12]4)[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3OCCCl)CC2)c1=O
Reactant: CCN
Solvent: CCO
Product: CCNCCOc1ccccc1C1(Nc2nccn(-c3cc(C(=O)NC4CC4)ccc3C)c2=O)CC1

Procedure:
The title product was prepared from 3-(3-(1-(2-(2-chloroethoxy)phenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 167e) and ethylamine (70% in water) in ethanol as co-solvent using a similar method to that described for example 167f.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]([F:50])([F:49])[C:41]([N:43]([CH2:45][C:46](O)=[O:47])[CH3:44])=[O:42]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[C:46](=[O:47])[CH2:45][N:43]([CH3:44])[C:41](=[O:42])[C:40]([F:49])([F:50])[F:39])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)C(=O)C(F)(F)F
Reactant: O=C(OCc1ccccc1)c1ccc(NCc2ccc(C3CCCCC3)cc2)cc1OCc1ccccc1
Product: CN(CC(=O)N(Cc1ccc(C2CCCCC2)cc1)c1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)C(F)(F)F
Yield: 97 %

Procedure:
Secondary aniline 4 was coupled to carboxylic acid 44 on a 3.17 mmol scale via General Procedure B to furnish 45 (2.07 g, 97%): δH (400 MHz, CDCl3) 1.35-1.44 (m, 5H, [Cy] CH2), 1.71-1.90 (m, 6H, [Cy] CH2), 3.17 (s, 3H, CH3), 3.79 (s, 2H, CH2), 4.84 (s, 2H, CH2), 4.97 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.65 (s, 1H, CH), 6.78 (dd, J=8.4 and 1.6 Hz, 1H, CH), 7.10-7.19 (m, 4H, CH), 7.29-7.43 (m, 10H, CH), 7.86 (d, J=8.4 Hz, 1H, CH); δC (100 MHz, CDCl3) 25.8, 26.6, 34.2, 44.0, 51.2, 52.6, 66.7, 70.4, 77.2, 113.9, 115.0, 117.6, 119.8, 126.8, 126.9, 127.7, 128.0, 128.3, 128.3, 128.4, 128.6, 132.9, 133.6, 135.5, 135.6, 144.6, 147.5, 157.0, 158.4, 165.1, 165.4; LRMS (ES+) calcd for [C39H39F3N2O5+Na] 695.27. found 695.36.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.Cl.N>[Fe].CO>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[C:7]=1[NH2:8]
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CO
Product: Nc1nccc(Cl)c1N

Procedure:
3.6 g of 2-amino-4-chloro-3-nitropyridine was added to 21 ml of methanol and 24 ml of concentrated hydrochloric acid, and the mixture was vigorously stirred. Powdery iron was added in small portions to the mixture. 10 min after the completion of the addition, the mixture was poured into an iced concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (CH2Cl2 :MeOH=20:1-10:1) to prepare 2.6 g of 4-chloro-2,3-diaminopyridine as a purplish white crystal.
Reaction SMILES: C1(=O)OC(=O)C=C1.[OH-].[Na+:9].[P:10]([CH2:14][NH:15][CH2:16][C:17]([OH:19])=[O:18])([OH:13])([OH:12])=[O:11].C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+:51].[Na+].[Na+].C(CN(CP(O)(O)=O)C(=O)/C=C\C(O)=O)(O)=O>CCOCC>[Na:9][Na:51].[P:10]([CH2:14][NH:15][CH2:16][C:17]([OH:19])=[O:18])([OH:13])([OH:12])=[O:11]
Reactant: [Na+]
Agent: O=C(O)/C=C\C(=O)N(CC(=O)O)CP(=O)(O)O
Agent: O=C(O)CNCP(=O)(O)O
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOCC
Product: [Na][Na]

Procedure:
A solution of the disodium salt of N-phosphonomethylglycine is prepared as described in Example I and 11.0 grams (0.11 mole) of finely ground maleic anhydride is added with stirring. Some sodium hydroxide is added to keep the pH at almost 9, and a small portion of ether is added to help dissolve particles of the anhydride. Stirring is continued for several days, and 2.0 or 4.0 gram portions of maleic anhydride are added until no further N-phosphonomethylglycine remains in the reaction mixture. During this period, small portions of sodium hydroxide are added as needed to maintain a pH of about 8. When reaction is complete, the mixture is filtered, rinsed with water, concentrated and then dried. The product, containing disodium maleate by-product, is obtained as a colorless glass, and it is identified by nuclear magnetic resonance (nmr) as the trisodium salt of N-carboxymethyl-N-(phosphonomethyl)maleamic acid. ##STR4##
Reaction SMILES: C[O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:39]=[CH:38][C:32]2[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=2[C:30]=1[CH2:40][CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[OH-].[Li+]>O1CCCC1>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]2[CH:39]=[CH:38][C:32]3[C:33](=[O:37])[CH2:34][CH2:35][O:36][C:31]=3[C:30]=2[CH2:40][CH2:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:6]=1[CH2:5][CH2:4][C:3]([OH:49])=[O:2])([OH:20])=[O:19]
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)O
Yield: 98 %

Procedure:
The 2-[6-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl)-2H-1-benzopyran-7-yl]oxy]hexyl]-6-[(6-methoxy-6-oxohexyl)oxy]benzenepropanoic acid methyl ester from the preceding example (0.38 g; 0.565 mmol) was saponified by stirring with 2 mL of 3N aqueous lithium hydroxide, in 15 mL of tetrahydrofuran for 24 hr, at room temperature. Work-up as in example 4 followed by flash-chromatography on silica gel (eluting with 96:3:1 chloroform-methanol-acetic acid) and recrystallization from hexane-ethyl acetate gave 0.36 g (98%) of the title compound as a colorless solid, mp 97°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:26])=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.Cl>C(#N)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:10][C:9]=3[N:26]=[C:31]2[C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]2[C:29]([OH:39])=[O:30])=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Agent: Cl
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a 100 mL round-bottomed flask was added N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.3 g, 2.9 mmol), cis-hexahydroisobenzofuran-1,3-dione (0.5 g, 2.9 mmol) and acetonitrile (27 mL). The resulting solution was heated to 90° C. After 3 h, the reaction was cooled to RT and HCl (15 mL, 6 N) was added and the mixture was heated to 90° C. for 15 h. The resulting mixture was cooled to RT and concentrated to dryness. The residue was partitioned between water (100 mL) and DCM (100 mL) and the mixture was stirred vigorously while the pH was adjusted to 4-5 using sat. NaHCO3. The organic layer was separated and the aqueous layer was further extracted with DCM (2×100 mL). The combine organic layers were dried with magnesium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (750 mg, 44%). MS (ESI): mass calcd. for C31H28BrN3O3, 569.13; m/z found, 570.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.36 (d, J=8.5, 1H), 8.05 (d, J=8.5, 1H), 7.93 (d, J=8.2, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4, 1H), 7.74 (d, J=8.5, 1H), 7.60 (ddd, J=8.1, 7.0, 1.1, 1H), 7.47-7.41 (m, 2H), 7.29 (d, J=2.3, 1H), 7.19 (d, J=8.8, 1H), 7.05 (d, J=8.5, 2H), 7.01 (dd, J=8.8, 2.4, 1H), 5.53-5.41 (m, 2H), 5.39 (s, 2H), 3.60-3.51 (m, 1H), 2.88-2.76 (m, 1H), 2.43-2.29 (m, 1H), 2.00-1.93 (m, 1H), 1.92-1.69 (m, 4H), 1.52-1.36 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([CH:26]([C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[NH2:27])[N:22]=1>>[CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:27][CH:26]([C:23]3[N:22]=[C:21]([CH3:20])[O:25][N:24]=3)[C:28]3([CH3:32])[CH2:31][O:30][CH2:29]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(N)C2(C)COC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: Cc1nc(C(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2(C)COC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (example 68a) and (5-methyl-1,2,4-oxadiazol-3-yl)-(3-methyloxetan-3-yl)methanamine (example 254b) as starting materials and isolated (47 mg, 55%); MS (ESI, m/z): 441.3 (M+H+).
Reaction SMILES: C(OC([N:8]([C:35]1[N:36]=[C:37]2[CH:43]=[CH:42][N:41]([S:44]([C:47]3[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=3)(=[O:46])=[O:45])[C:38]2=[N:39][CH:40]=1)[CH2:9][C:10]([C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]3[C:23]2=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:19])[CH2:13]1)=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[S:44]([N:41]1[C:38]2[N:39]=[CH:40][C:35]3[N:36]([C:10]([C@@H:12]4[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][CH:22]5[C:23]6[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=6[C:29]6[C:34]5=[CH:33][CH:32]=[CH:31][CH:30]=6)=[O:19])[CH2:13]4)=[CH:9][N:8]=3)[C:37]=2[CH:43]=[CH:42]1)([C:47]1[CH:53]=[CH:52][C:50]([CH3:51])=[CH:49][CH:48]=1)(=[O:45])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)[C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)C(=O)OC(C)(C)C)cnc32)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc([C@@H]4CCCN(C(=O)OCC5c6ccccc6-c6ccccc65)C4)n23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.9 %

Procedure:
A mixture of (R)-(9H-fluoren-9-yl)methyl 3-(2-(tert-butoxycarbonyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)acetyl)piperidine-1-carboxylate (0.20 g, 0.27 mmol), TFA (1.0 mL, 13 mmol) and TFAA (1.0 mL, 7.1 mmol) was stirred at about 25° C. for about 16 h. The reaction mixture was partitioned between EtOAc (50 mL) and aqueous saturated NaHCO3 (2×50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (R)-(9H-fluoren-9-yl)methyl 3-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidine-1-carboxylate as a clear oil (0.17 g, 99%): LC/MS (Table 2, Method a) Rt=2.68 min; MS m/z: 618 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13](O)(=O)CC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCC(=O)O
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(C(C)C(=O)O)cc1
Yield: 73 %

Procedure:
The titled compound was prepared from p-methoxyphenylacetic acid in 73% yield in the same manner as the preparation of 22-chlorophenyl)propionic acid in Example 184a. MS (ESI) 181 (MH+)
Reaction SMILES: [H-].[Na+].[OH:3]/[N:4]=[C:5](/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)\[CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:3]/[N:4]=[C:5](/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)\[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:41][CH:40]=1
Reactant: CCOC(=O)CCC/C(=N\O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCC(=O)O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Sodium hydride (60% in oil, 153 mg) was added under a nitrogen atmosphere to a solution of ethyl E-5-hydroxyimino-5-phenylpentanoate (751 mg) and 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g) in N,N-dimethylformamide (10 ml) at room temperature and the mixture was stirred for 1 hour. After adding 1N HCl (5 ml), aqueous sodium bicarbonate was added, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to column chromatography on silica gel to obtain an oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v). This oil was dissolved in tetrahydrofuran (20 ml)-methanol (10 ml), and 1N aqueous solution of sodium hydroxide (10 ml) was added and the mixture was stirred at room temperature for 2 hours. 1N HCl (10.5 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystal was recrystallized from ethyl acetate-hexane to obtain E-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-5-phenylpentanoic acid (1.24 g, yield 80%) as colorless crystals. m.p. 129-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH2:19][NH:18]2)[CH:5]=[C:6]([Cl:16])[C:7]=1[S:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Sc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(Sc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1

Procedure:
20 g of 2-[3,5-dichloro-4-(4-methylthio-phenoxy)-phenyl]-1,2,4-triazine-3,5-(2H,4H)-dione were dissolved in 200 ml of hot glacial acetic acid. 25 g of tin(II) chloride·2H2O and then 100 ml of concentrated hydrochloric acid were added, and the mixture was subsequently heated for 4 hours under reflux. After cooling, the product was filtered off with suction, washed with water until neutral and recrystallized from 2-methoxyethanol; melting point 239° C.
Reaction SMILES: C(ON=O)(C)(C)C.N[CH:9]1[N:34]([C:35]#[N:36])[CH:12]2[CH:13]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([Br:33])[CH:24]=3)[CH:14]=[C:15]3[C:20]([O:19][C:18](=[O:21])[C:17]([CH3:22])=[CH:16]3)=[C:11]2[O:10]1.[BH4-].[Na+].CCOC(C)=O>C1COCC1.ClCCl>[Br:33][C:25]1[CH:24]=[C:23]([CH:13]2[CH:12]3[N:34]([C:35]#[N:36])[CH2:9][O:10][C:11]3=[C:20]3[C:15]([CH:16]=[C:17]([CH3:22])[C:18](=[O:21])[O:19]3)=[CH:14]2)[CH:28]=[C:27]([O:29][CH3:30])[C:26]=1[O:31][CH3:32]
Reactant: COc1cc(C2C=c3cc(C)c(=O)oc3=C3OC(N)N(C#N)C32)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C2C=c3cc(C)c(=O)oc3=C3OCN(C#N)C32)cc(Br)c1OC
Reaction time: 2 h
Yield: 51 %

Procedure:
At 0° C., tert-butylnitrite (62 μL, 0.52 mmol) was added to 2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-methyl-8-oxo-4H-oxazolo[4,5-h]chromene (20 mg, 0.044 mmol) in dry THF (1 mL) and was stirred at this temperature for 2 h. Sodium borohydride (19.8 mg, 0.52 mmol) was added and the reaction was stirred at 0° C. for 3 h. Reaction was quenched with NH4Cl saturated aqueous solution (1 mL) and the mixture was partitioned between water (2 mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (2×5 mL). The organic layers were combined, washed with saturated NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated to a yellow oil. The product was isolated by flash chromatography using a 12S SiO2 system by Biotage, Inc., Charlottesville, Va., using 1 to 2% EtOAc in dichloromethane to yield 10 mg (85%) of 4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-methyl-8-oxo-4H-oxazolo[4,5-h]chromene as a light yellow solid. 1H NMR (Acetone-d6) 7.80 (d, J=1.2 Hz, 1H), 7.13-7.11 (m, 2H), 6.99-6.96 (m, 2H), 5.00 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.39 (s, 3H).