Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Li+].[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=1.[H][H].C1(=O)O[CH2:18][CH2:17][O:16]1>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:18][CH2:17][OH:16])=[C:6]([CH3:12])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: O=C1OCCO1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C)c1OCCO
Temperature: 150 °C
Yield: 64.4 %

Procedure:
Lithium hydride (200 mg) was added to a stirred solution of 4-bromo-2,6-dimethylphenol (65 g) in DMF at ambient temperature. When evolution of hydrogen had ceased, ethylene carbonate (31.9 g) was added and the mixture was heated at 150° C. for 12 hours. The DMF was removed by evaporation and the cooled residue was dissolved in ethyl acetate (500 ml). The ethyl acetate solution was washed with water (2×100 ml) and then with saturated brine (100 ml), dried (MgSO4) and evaporated. The residue was crystallised from methanol to give 2-(4-bromo-2,6-dimethylphenoxy)ethanol (51 g), m.p. 47-48° C. NMR (CDCl3): 2.21(6H,s), 3.86(2H,m), 3.93(2H,m), 7.12(2H,s).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCCc1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)-phenyl]ethane (1.7 g, 8.09 mmol) in acetic acid (10 mL) was added, dropwise, concentrated HNO3 (4.5 mL). This was stirred at room temperature for 30 min. The reaction mixture was poured into water (100 mL). The precipitated solid was filtered, washed with water and dried under high vacuum to afford 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane (1.8 g, 88% yield).
Reaction SMILES: Cl.[F:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][C@H:8]2[CH2:12][NH:11][C@H:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)=[O:14])[CH2:9]2)=[CH:5][CH:4]=1.[N:32]1[N:33]([CH2:37][C:38](O)=[O:39])[N:34]=[CH:35][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:32]1[N:33]([CH2:37][C:38]([N:11]2[CH2:12][C@H:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:31][CH:30]=3)[CH2:9][C@H:10]2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[O:14])=[O:39])[N:34]=[CH:35][CH:36]=1
Reactant: O=C(O)Cn1nccn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(F)cc2)CN1C(=O)Cn1nccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.3 %

Procedure:
A round bottom flask was charged with (2S,4R)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide hydrochloride (150 mg, 0.37 mmole, 1 eq), prepared as in Reference 6, 2H-1,2,3-triazole-2-ylacetic acid (51 mg, 0.40 mmole, 1.1 eq), HATU (152 mg, 0.40 mmole, 1.1 eq) and DMF (1 mL). DIEA (195 μL, 1.11 mmole, 3 eq) was added and the mixture stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized water. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organics were washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue via flash chromatography (silica, 5% MeOH, 95% EtOAc). Clean fractions were combined and concentrated in vacuo to afford Compound 50, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-4-(4-fluorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (171 mg, 89% yield), as a white solid. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.80 (s, 2H), 7.58-7.51 (m, 2H), 7.34-7.07 (m, 6H), 7.04-6.90 (m, 4H), 5.48 (q, 2H), 4.53-4.46 (m, 1H), 3.85-3.76 (m, 1H), 2.77-2.61 (m, 3H), 2.03-1.86 (m, 2H). MS (EI) for C28H25F2N5O3. found 517.9 (MH+).
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C:29]1([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C:29]1([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)C1(N)CCCCC1
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(NC2(C(=O)N(C)C)CCCCC2)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 0.72 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 75-3 (2.55 mmol, crude form) as starting materials, 0.24 g of the title compound (pale yellow solid) was obtained by a similar method to Step 4-2.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=O)[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][N:19](C)C)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:30]N>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][NH:19][N:30]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C(NCc1ccccc1)c1cc(-c2n[nH]cc2-c2ccccc2)c[nH]1
Reaction time: 12 h

Procedure:
To a solution of compound 3 (1 equivalent) in ethanol, at ambient temperature, was added hydrazine hydrate (3 equivalents) and the resulting mixture heated at reflux. After 12 hours, the solvent was evaporated and the crude product purified by preparatory HPLC (reverse phase; 10→90% MeCN in water; 15 minutes) to afford the desired compound II-5. LC/MS (M+1) 343.3, (M−1) 341.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][C:19](Cl)=[O:20].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([N:13]1[CH2:14][CH2:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)([C:16]#[N:17])[CH2:11][CH2:12]1)(=[O:20])[CH3:18]
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(C#N)(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 4-(4-nitro-phenyl)-piperidine-4-carbonitrile (as prepared in the previous step) in CH2Cl2 is treated with CH3COCl and DIEA. The mixture is washed with water, and the organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O)=[C:4]([CH3:15])[CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.BrC1C=CC(NC(=O)CC(N(C2CCCCC2)C(NC2CCCCC2)=O)=O)=C(C)C=1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([CH3:15])[CH:3]=1
Reactant: Sc1ccccc1
Reactant: Cc1cc(Br)ccc1NC(=O)CC(=O)O
Agent: Cc1cc(Br)ccc1NC(=O)CC(=O)N(C(=O)NC1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1NC(=O)CC(=O)Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred mixture of 5.44 grams (0.02 mole) of 3-[(4-bromo-2-emthylphenyl)amino)-3oxopropanoic acid prepared in Example V (Compound No. 97) and 2.31 grams (0.02 mole) of thiophenol in approximately 100 milliliters of dry tetrahydrofuran in an oven-dried reaction flask was fed a solution of 4.13 grams (0.02 mole) of 1,3-dicyclohexylcarbodiimlde in about 25 milliliters of dry tetrahydrofuran, while cooling the reaction mixture in an ice-water bath. On completing the feed the ice bath was removed and the mixture stirred for about one hour following which the precipitated 1,3-dicyclohexylurea by-product (2.5 grams) was removed by filtration. Vacuum stripping the filtrate gave a solid which was recrystallized from acetone to give a compound, melting point 184° C.-187° C., which proved to be 1-(3-[(4-bromo2-methylphenyl)amino]-3-oxopropanoyl)-1,3-dicyclohexylurea. The filtrate from this was concentrated and flash chromatographed (7:3 hexane:ethylacetate, silica column) to give 2.83 grams (0.008 mole) of S-phenyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanethioate having a melting point of 133° C.-135° C. Elemental analysis of the product indicated the following:
Reaction SMILES: C(S[C@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50])C.[Cl:52]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:52][C@@H:4]1[N:7]([C:8](=[C:22]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([S:38][C:39]3[CH:44]=[C:43]([Cl:45])[C:42]([Cl:46])=[CH:41][C:40]=3[Cl:47])=[O:37])=[CH:32][CH:31]=2)[C:23](=[O:28])[C:24]([CH3:25])([CH3:27])[CH3:26])[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[S:10])[C:6](=[O:48])[C@@H:5]1[C@H:49]([OH:51])[CH3:50]
Reactant: CCS[C@@H]1[C@@H]([C@@H](C)O)C(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(C(=O)Sc2cc(Cl)c(Cl)cc2Cl)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=S)OCc2ccc([N+](=O)[O-])cc2)=C(Oc2ccc(C(=O)Sc3cc(Cl)c(Cl)cc3Cl)cc2)C(=O)C(C)(C)C)[C@H]1Cl
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a stirred solution of 1.26 g of 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-1-yl]-3-[4-(2,4,5-trichlorophenylthio-(carbonyl))-phenoxy]-3-trimethylacetylthiopropenoate in 30 ml of dry chloroform at -40° C. was added a solution of 1.83 mmol chlorine in 4 ml of carbon tetrachloride, and the solution was stirred for 30 minutes. The reaction mixture was allowed to reach room temperature and evaporated to dryness. Chromatography of the residue (silica gel, hexane/ethyl acetate mixtures as eluant) gave the title compound as a pale yellow foam (0.706 g). νmax (CHCl3) 1784 cm-1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:12][C:13]([Cl:18])=[N:14][C:15]=1[CH2:16][CH3:17]>CN(C)C=O>[ClH:18].[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:12][C:13]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:14][C:15]=1[CH2:16][CH3:17]
Reactant: CNc1ccccc1
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Product: CCc1nc(N(C)c2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 55.4 %

Procedure:
After N-methylaniline(0.44 ml, 4.06 mmol) was added to a mixed solution of 5-methyl-6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(0.80 g, 2.65 mmol) and dimethylformamide(5 ml), 0.60 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2](C)C.FC1C=C(C)C=CC=1[N+]([O-])=[O:14].[CH2:17]([NH:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:23]=1[NH2:24])[CH:18]([CH3:20])[CH3:19].N[C:31]1[S:32]C=[CH:34][N:35]=1>>[CH2:17]([NH:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:23]=1[NH2:24])[CH:18]([CH3:20])[CH3:19].[CH2:17]([NH:21][C:22]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:23]=1[NH:24][C:34]([NH:35][C:31]1[S:32][CH:2]=[CH:1][N:5]=1)=[O:14])[CH:18]([CH3:20])[CH3:19]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: Nc1nccs1
Reactant: CC(C)CN
Agent: Cc1ccc(N)c(NCC(C)C)c1
Product: Cc1ccc(NC(=O)Nc2nccs2)c(NCC(C)C)c1
Yield: 65 %

Procedure:
2-Isobutylamino-4-methyl-aniline (0.61 g, 69%) was prepared from isobutylamine (0.73 g, 10.0 mmol) and 3-fluoro-4-nitrotoluene (0.77 g, 5.0 mmol) following the general procedure W. 1-(2-Isobutylamino-4-methyl-phenyl)-3-thiazol-2-yl-urea (196 mg, 65%) was prepared from 2-Isobutylamino-4-methyl-aniline (178 mg, 1.0 mmol) and 2-aminothiazole, (100 mg, 1.0 mmol) following the general procedure D.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[CH2:13]([O:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH3:14]>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:16]([O:15][CH2:13][CH3:14])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CCONCc1ccc(F)cc1
Product: CCON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 92 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with O-ethyl-N-4-fluorobenzyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as white crystals (92% yield): mp 95–96° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.07 Hz, CH3), 1.77 (6H, s, CH3), 3.90 (2H, q, J=7.07 Hz, OCH2), 4.81 (2H, s, NCH2), 6.41 (1H, s, CH), 7.03 (2H, m, aromatics), 7.37 (2H, m, aromatics). Anal. calcd for C16H18FNO5: C, 59.43; H, 5.61; N, 4.33. Found: C, 59.50; H, 5.60; N, 4.17.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:27])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1.CSC.[Cu](Br)Br>[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:27])[C@H:21]([Br:28])[CH:22]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CCCC[Mg]Cl
Agent: Br[Cu]Br
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCC(CCCC)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
A slurry of copper bromide (I) dimethyl sulfide complex (5.132 g, 24.967 mmol) in THF (60 mL) and dimethyl sulfide (30 mL) as a co-solvent was cooled to −40° C. and n-butyl magnesium chloride (25 mL, 49.93 mmol) was added dropwise for 10 min and stirred for 20 min while warning to −15° C. The black slurry was cooled to −40° C. and (4R)-4-benzyl-3-[(E)-2-heptenoyl]-1,3-oxazolidin-2-one (6 g, 20.80 mmol) was added dropwise over 10 min as a solution in THF (20 mL) at −40° C. The reaction was let warm up to 25° C. overnight (20 h). N-Bromosuccinimide (7.407 g, 41.61 mmol) was added portionwise to a cold −78° C. solution of the black slurry. It was allowed to warm to 0° C. and was stirred for an additional 3 h. The reaction was quenched with a 1:1 solution of saturated ammonium carbonate and 0.5 N potassium bisulfate. The black slurry became greenish to blue. A precipitate formed (light blue). It was filtered. The mother liquor was diluted with ethyl acetate (150 mL) and the organic was dried over MgSO4, filtered, concentrated to obtain (4R)-4-benzyl-3-[(2R)-2-bromo-3-butylheptanoyl]-1,3-oxazolidin-2-one as a crude semi-solid (green) (8.49 g, 96.15%). Mass Spectrum (−ESI): 423 (M−H)−.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22]>CN(C=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:17][C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23][CH3:24])=[O:22])[CH2:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCCN2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2CCOc3cc([N+](=O)[O-])ccc32)c1
Yield: 102.5 %

Procedure:
The same operation as in Example (90a) was performed using 7-nitro-2,3-dihydro-4H-1,4-benzoxazine (described in Higuchi, Robert I.; Arienti, Kristen L.; Lopez, Francisco J.; Mani, Neelakhanda S.; Mais, Dale E.; Caferro, Thomas R.; Long, Yun Oliver; Jones, Todd K.; Edwards, James P.; Zhi, Lin; Schrader, William T.; et al.; J. Med. Chem.; 50; 10; 2007; 2486-2496, 0.6 g, 3.3 mmol), sodium hydride (55% content, 145 mg, 3.3 mmol), methyl 3-bromomethylbenzoate (0.76 g, 3.3 mmol) and DMF (50 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/1) gave 1.11 g of the title compound as a deep yellow solid (100%).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.O.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1N1CCNCC1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:7]1[CH2:6][CH2:5][N:4]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:3][CH2:2]1)#[N:23]
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: N#Cc1ccccc1N1CCNCC1
Solvent: O
Product: N#Cc1ccccc1C1CCN(c2cc(-c3ccccn3)cn(-c3ccccc3)c2=O)CC1
Temperature: 130 °C
Yield: 41.7 %

Procedure:
29 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 200 mg of 1-(2-cyanophenyl)piperazine, followed by heating at 130° C. for 72 hours. After the reaction solution was cooled to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 8 mg of the title compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[CH:34]([S:36]([N:39]1[CH2:42][C:41]([F:44])([F:43])[CH2:40]1)(=[O:38])=[O:37])=[CH2:35]>>[F:44][C:41]1([F:43])[CH2:40][N:39]([S:36]([CH2:34][CH2:35][N:8]2[CH2:11][CH:10]([C:12]3[CH:33]=[CH:32][C:15]4[C:16]5[N:17]=[C:18]([C:24]6[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=6)[S:19][C:20]=5[CH2:21][CH2:22][O:23][C:14]=4[CH:13]=3)[CH2:9]2)(=[O:37])=[O:38])[CH2:42]1
Reactant: C=CS(=O)(=O)N1CC(F)(F)C1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(=O)(=O)N4CC(F)(F)C4)C3)ccc1-2

Procedure:
Following the procedure for 320, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and 1-ethenesulfonyl-3,3-difluoro-azetidine were reacted to give 454 isolated as a white solid (139 mg, 84%). LCMS: RT=8.30 min, [M+H]+=551. 1H NMR δ (ppm) (CDCl3): 8.32 (1 H, d, J=8.18 Hz), 7.89 (1 H, s), 7.08 (1 H, dd, J=8.21, 1.87 Hz), 6.97 (1 H, d, J=1.84 Hz), 5.93-5.83 (1 H, m), 4.38 (2 H, t, J=5.05 Hz), 4.31 (4 H, t, J=12.10 Hz), 3.76 (2 H, t, J=6.86 Hz), 3.75-3.63 (1 H, m), 3.43-3.36 (2 H, m), 3.23 (2 H, t, J=6.61 Hz), 3.11 (2 H, t, J=7.01 Hz), 2.92 (2 H, t, J=7.00 Hz), 1.60 (6 H, d, J=6.63 Hz)
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH2:15])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20].O.[C:24](Cl)(=[O:26])[CH3:25]>CC(N(C)C)=O>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[C:13]([I:14])=[C:12]([NH:15][C:24](=[O:26])[CH3:25])[C:11]([I:16])=[C:10]([C:17]([OH:19])=[O:18])[C:9]=1[I:20]
Reactant: CNC(=O)CCNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: CC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CNC(=O)CCNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)O)c1I
Yield: 58.8 %

Procedure:
99.5 g. (0.15 mole) of N-(3-carboxy-5-amino-2,4,6-triiodobenzoyl)-β -alanine methylamide . 1.1 H2O (IVf), m.p. 250°-252° C. (decomposition) in 190 ml. of dimethylacetamide yield, after reaction with 40.0 ml. of acetyl chloride analogously to Example 1, 60.4 g. (58.8%) of the desired compound. A sample for analysis is purified in alcohol by way of the dimethylammonium salt; m.p. 288°-289° C. (under decomposition).
Reaction SMILES: [C:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[C:7]([O:18]C(=O)C)[N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)(OC)=[O:2].[H-].C([Al+]CC(C)C)C(C)C.C(=O)=O.CC(C)=O.O>O1CCCC1>[CH:1]([C:5]1[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH:8]=[C:7]([OH:18])[N:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:2]
Reactant: COC(=O)c1nc(OC(C)=O)cc2c1[nH]c1ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C=O
Agent: [H-]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=Cc1nc(O)cc2c1[nH]c1ccccc12
Yield: 9.9 %

Procedure:
In 50 ml of dry tetrahydrofuran were dissolved 135 mg of the product of Example 6, followed by addition of 2 ml of di-isobutyl-aluminum hydride. The reaction mixture was allowed to stand with dry ice-acetone cooling for 2 hours and then poured into water. The precipitated reagent was removed, the solvent removed by distillation and the residue recrystallized from water-methanol to yield 10 mg of the title compound melting at 290°-295° C. (decomp.). Mol. wt. (based on mass spectrum) 212. IR absorption spectrum: 3300, 1640, 1620, 1600 cm-1. UV absorption spectrum (MeOH): 420, 292, 282, 262 mμ. NMR spectrum (DMSO-d6): 10.1 ppm, 1H (CHO), 7.7 ppm, 1H (4-H), 8.2 ppm, 1H, 7.2-7.6 ppm, 3H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:35][C:36]#[CH:37]>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:37][C:36]#[CH:35])[C:9]2[C:10](=[O:29])[N:11]([CH3:28])[N:12]=[C:13]([O:15][CH2:16][C@H:17]3[CH2:19][C@@H:18]3[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)[CH:14]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CNc2cc(OC[C@H]3C[C@@H]3c3ccc(OC)cn3)nn(C)c2=O)cc1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C#CCN(Cc1ccc(OC)cc1)c1cc(OC[C@H]2C[C@@H]2c2ccc(OC)cn2)nn(C)c1=O
Reaction time: 0.17 h

Procedure:
To a solution of 4-(4-methoxybenzylamino)-6-(((1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl)methoxy)-2-methylpyridazin-3(2H)-one (210 mg, 0.50 mmol) in THF (20 mL) was added NaH (30 mg, 0.75 mmol) at 0° C. After stirred for 10 min, 3-bromoprop-1-yne (118 mg, 1.00 mmol) was added. The mixture was stirred for 2 h at room temperature and then diluted with H2O (20 mL) and EtOAc (50 mL). The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (4/1) to give the title compound as oil. ESI-MS: 461.2 (M+H)+. 1H NMR (400 MHz, MeOD) δ 7.95 (d, 1H), 7.21-7.18 (m, 3H), 7.07 (d, 1H), 6.78 (d, 2H), 6.19 (s, 1H), 4.50 (s, 2H), 4.10-3.94 (m, 4H), 3.75 (s, 3H), 3.74 (s, 3H), 3.72 (s, 3H), 2.61 (s, 1H), 2.00-1.96 (m, 1H), 1.68-1.63 (m, 1H), 1.11-1.00 (m, 1H), 0.95-0.97 (m, 1H).