Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12](Cl)=[O:13]>C1COCC1>[CH3:1][NH:2][C:12]([C:4]1[S:3][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=1)=[O:13]
Reactant: CN
Reactant: O=C(Cl)c1cc2ccccc2s1
Solvent: C1CCOC1
Product: CNC(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred solution of 2.0 M methylamine in THF (60 mL) and THF (60 mL) was added dropwise at 0° C. a solution of benzothiophene-2-carbonyl chloride (10.8 g, 55 mmole) in THF (50 mL) over 15 minutes. After the addition the reaction was allowed to warm to RT then was concentrated under vacuum. Trituration with a cold solution of 4:1 H2O/methanol (50 mL), filtration, and drying under vacuum gave the title compound (10.35 g, 98%) as a white solid: MS (ES) m/e 191.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:10]([C:20]2[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[OH2:27].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[C:3]([N:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:10]([C:20]2[S:21][CH:22]=[C:23](/[CH:25]=[CH:29]/[C:30]([O:31][CH2:32][CH3:28])=[O:27])[N:24]=2)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: C1CCOC1
Reactant: COc1ccc(-c2c(-c3nc(C=O)cs3)cnn2C(C)(C)C)cc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
To a solution of triethyl phosphonoacetate (0.026 ml, 0.13 mmol) in THF (2.0 mL) was added sodium hydride (55 wt % paraffin oil, 5.15 mg, 0.13 mmol) at 0° C., and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added a solution of the compound (40 mg, 0.12 mmol) obtained in step 3 in THF (2.0 mL) at 0° C., and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was crystallized from diethyl ether-hexane to give ethyl(E)-3-(2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acrylate (12.2 mg, 0.030 mmol, 25.3%) as a white powder.
Reaction SMILES: [CH2:1]([Si]1(Cl)N(C)[C@@H](C)[C@H](C2C=CC=CC=2)O1)[CH:2]=[CH2:3].[CH:18](=[N:25][NH:26][C:27](=[O:29])[CH3:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO>C(Cl)Cl>[C:19]1([C@H:18]([NH:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:3][CH:2]=[CH2:1])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)NN=Cc1ccccc1
Reactant: C=CC[Si]1(Cl)O[C@@H](c2ccccc2)[C@H](C)N1C
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@@H](NNC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
Enantioselective allylation of acetic acid benzylidene-hydrazide (8) to give (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide: To a cooled (10° C.) solution of (4S,5S)-2-Allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (9.90 g, 37.0 mmol) in CH2Cl2 (300 mL) was added acetic acid benzylidene-hydrazide (5.00 g, 30.8 mol) as a solid. The resulting solution was stirred for 16 hours and methanol (40 mL) was then added. After 15 min all volatiles were removed by distillation and the residue was diluted with EtOAc (150 mL) and H2O (500 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2×150 mL). The combined organic layers were washed with H20 and brine, dried (MgSO4), filtered and concentrated. Analysis of the residue by HPLC revealed an ee of 87%. The residue was dissolved in boiling toluene (80 mL) and the solution was then cooled to ambient temperature. Pentane (380 mL) was layered on top of the toluene solution and the resulting biphasic solution was allowed to stand for 16 hours. The resulting crystalline solid precipitate was filtered, washed (pentane:toluene (5:1)) and then dried in vacuo to give 5.04 g (80%) of (1R)-acetic acid N′-(1-phenyl-but-3-enyl)-hydrazide in 98% ee.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH2:22])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([NH:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH3:21])[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: CC(N)c1cc(Cl)cc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cc(Cl)cc(Cl)c1
Yield: 11 %

Procedure:
A mixture of 2,4-difluoro-nitrobenzene (3.13 mmol), 1-(3,5-dichlorophenyl)ethanamine (3.13 mmol) and N,N-diisopropylethylamine (6.3 mmol) were stirred at 45° C. in dry acetonitrile (25 mL) for 16 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and purified by silica chromatography in 20% ethyl acetate in hexanes to collect the title compound (11% yield). 1H NMR (400 MHz, CDCl3): δ 9.23 (s, 1H), 7.87 (t, 1H), 7.28 (s, 1H), 7.19 (s, 2H), 6.41 (t, 1H), 6.11 (d, 1H), 4.51 (m, 1H), 1.62 (d, 3H).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>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:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Fc1cccnc1Br
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: [Na+]
Product: N#Cc1ccc(-c2ncccc2F)cc1
Temperature: 80 °C
Yield: 97.5 %

Procedure:
A mixture of 2-bromo-3-fluoropyridine (1.05 g, 6.0 mmol), 4-cyanophenylboronic acid (0.882 g, 6.0 mmol), Pd(PPh3)4 (0.138 g, 0.12 mmol), and aqueous sodium carbonate solution (2M, 6 mL), in dioxane (6 mL) was degassed for 15 minutes. The mixture was sealed, heated to 80° C. for 12 hours, washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified by chromatography to yield 4-(3-fluoropyridin-2-yl)benzonitrile (1.16 g, 89%).
Reaction SMILES: O.[F:2][C:3]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=2[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:5]([N+:35]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:35][C:5]1[CH:4]=[C:3]([F:2])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:6]=1[O:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
To a mixture of 19 g of iron powder, 60 ml of acetic acid, and 6 ml of water was added dropwise a solution of 19.12 g of methyl [2-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]-2-nitrophenoxy}phenoxy]acetate in 60 ml of acetic acid under ice cooling. After completion of the dropwise addition, the temperature was increased to room temperature, and the mixture was stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The mixture was washed with water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel chromatography to give 15.16 g of methyl [2-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:25])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CN1CCC(OC(=O)CCN)CC1
Agent: Cl
Product: CN1CCC(OC(=O)CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)CC1

Procedure:
The title compound was prepared from 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 1-methylpiperidin-4-yl β-alaninate hydrochloride in a similar manner as described for Example 164. Mass Spectrum: [M+H]+ 450.12, [M−H]− 448.23.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:27]([OH:35])[C@H:26]3[OH:36])=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:53]1(C)[C:54](S(O)(=O)=O)=CC=C[CH:58]=1.[OH-].[NH4+]>CC(C)=O.COC(OC)(C)C>[CH2:1]([O:8][C:9](=[O:52])[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@H:25]3[C@H:26]4[C@H:27]([O:35][C:53]([CH3:54])([CH3:58])[O:36]4)[C@@H:28]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:29]3)=[C:18]([NH:37][CH2:38][CH:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@H](O)[C@@H]1O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: COC(C)(C)OC
Solvent: CC(C)=O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OCc5ccccc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of {(R)-1-[9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid benzyl ester (0.63 g, 0.89 mmol) in acetone (10 ml) and 2,2-dimethyloxypropane (5 ml) is treated with toluenesulfonic acid (ca. 60 mg) and then stirred at room temperature overnight. The mixture is basified using ammonium hydroxide and the solvent is removed in vacuo. The crude product is partitioned between DCM and water and the organic portion is washed with brine, dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. [MH+ 745].
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].C([N:11]([CH2:13][CH3:14])[NH2:12])C.[CH3:15][C:16](O)=O>>[Br:1][C:2]1[C:3](=[O:4])[N:11]([CH2:13][CH3:14])[N:12]([CH2:15][CH3:16])[C:6](=[O:8])[CH:7]=1
Reactant: O=C1C=C(Br)C(=O)O1
Reactant: CC(=O)O
Reactant: CCN(N)CC
Product: CCn1c(=O)cc(Br)c(=O)n1CC
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of monobromomaleic anhydride (177 mg, 1.0 mmol) and N,N-diethylhydrazine (88 mg, 1.0 mmol) in glacial AcOH (3 mL) was heated at 130° C. for 16 h. The solvent was removed in vacuo and the crude residue purified by column chromatography (neat CH2Cl2-5% MeOH/CH2Cl2) to give 4-bromo-1,2-diethyl-1,2-dihydro-pyridazine-3,6-dione as a yellow solid (159 mg, 0.64 mmol, 64%): 1H NMR (600 MHz, CDCl3) δ 7.31 (s, 1H), 4.14 (q, J=7.0 Hz, 2H), 4.07 (q, J=7.0 Hz, 2H), 1.26 (t, J=7.0 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 156.2 (s), 154.3 (s), 136.0 (d), 133.7 (s), 41.9 (t), 40.7 (t), 13.3 (q), 13.3 (q); IR (solid) 3058, 2979, 2938, 1631, 1595 cm−1; LRMS (CI) 249 (100, [M81Br+H]+), 247 (100, [M79Br+H]+); HRMS (CI) calcd for C8H12BrN2O2 [M+H]+ 249.0082, observed 249.0086.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[N:19]1([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: C1CNCCNC1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Product: Clc1ccc(OCCOc2nccnc2N2CCCNCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine* (150 mg, 0.53 mmol) and homopiperazine (287 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 128 mg (69%) of the title product. HRMS m/z calcd for C17H2IClN4O2(M)+ 348.1353, found 348.1353. Anal. (C17H21ClN4O2) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=1.[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C[CH2:43][O:44]C(C)=O.CCCCCC>>[C:27]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:31][C:30]([C:43]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:9][C@@H:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([NH:13][CH2:14][C:15]#[N:16])=[O:12])=[CH:4][CH:3]=2)=[O:44])=[CH:29][CH:28]=1
Reactant: CCOC(C)=O
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Solvent: CCCCCC
Product: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(C(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)NCC#N

Procedure:
Using the same procedures as described for the example 50, (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-N-(cyanomethyl)-4-methylpentanamide (105 mg, 0.253 mmol) was reacted with 1,1′-biphenyl-4-ylboronic acid (50 mg, 0.253 mmol, 1 eg) to give the title compound after chromatography with 20% EtOAc/hexane.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[N:26]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][S:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)(=[O:34])=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)N1CCOCC1

Procedure:
The title compound, white solid (5.4 mg, 13.2%), MS (ISP) m/z=480.2 [(M+H)+], was prepared in accordance with the general method of example 78 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (31.2 mg, 85 mmol) and morpholine-4-sulfonyl chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:13]2([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[CH2:4]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl>[OH:19][C:13]1([C:3]2([CH2:2][NH:1][C:28](=[O:29])[O:30][CH2:31][CH3:32])[C:6]3[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=3[CH2:4]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc2c(c1)C(CN)(C1(O)CCCCC1)C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC1(C2(O)CCCCC2)Cc2ccc(OC)cc21
Reaction time: 24 h

Procedure:
A solution of 2 g (7.65 mM) of the compound obtained in Step D and 2.6 ml (19.8 mM) of triethylamine in 100 ml of methylene chloride is poured into a solution, cooled to 0° C., of 0.61 ml (7.65 mM) of ethyl chloroformate in 50 ml of methylene chloride. Stirring is carried out for 24 hours at room temperature, and the mixture is siluted with water and extracted with methylene chloride. The organic phases are washed first with 1N HCl and then with water until neutral and finally dried over MgSO4 to yield, after evaporation, 2.2 g of the expected product.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:40]=[C:41](F)[CH:42]=1)[CH2:5][C@H:6]([C:25](N1[C@@H](CC2C=CC=CC=2)COC1=O)=O)[C@@H:7]([C@H:9]1[CH2:13][C@@H:12](OCC=C)CN1C(OC(C)(C)C)=O)O.[F:44][C:45]1[CH:46]=[C:47]([CH:68]=[C:69]([F:71])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([CH:54]2[CH2:59][O:58][CH2:57][CH2:56][N:55]2C(OC(C)(C)C)=O)[O:52][C:51](=[O:67])[NH:50]1.FC1C=C(C=C(F)C=1)C[C@@H]([C@@H](C1COCCN1C(OC(C)(C)C)=O)O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:71][C:69]1[CH:68]=[C:47]([CH:46]=[C:45]([F:44])[CH:70]=1)[CH2:48][C@H:49]1[C@@H:53]([C@H:54]2[CH2:59][C@H:57]([OH:58])[CH2:56][N:55]2[CH:5]([C:4]2[CH:3]=[CH:2][CH:42]=[CH:41][CH:40]=2)[C:6]2[CH:7]=[CH:9][CH:13]=[CH:12][CH:25]=2)[O:52][C:51](=[O:67])[NH:50]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1[C@H]1OC(=O)N[C@H]1Cc1cc(F)cc(F)c1
Reactant: C=CCO[C@@H]1C[C@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCOCC1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Step D (5): tert-Butyl 3-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)morpholine-4-carboxylate. To a solution of (2S,3S)-2-(3,5-difluorobenzyl)-3-(4-(tert-butoxycarbonyl)morpholin-3-yl)-3-hydroxypropanoic acid (step D (4)), 1.6 g, 4. mmol) in toluene (100 mL) was added diphenylphosphoryl azide (1.65 g, 6 mmol) and triethyl amine (1.01 g, 10 mmol). This reaction mixture was stirred at 80° C. for 4 h. Ethyl acetate (500 mL) was added. The mixture was washed with sodium carbonate solution, H2O, dried over Na2SO4 and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 800 mg of the title compound: MS (ESI) (M−H)− 397.12.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10]C2CCCCO2)[CH:7]=[C:6]([B:17]2[O:21]C(C)(C)[C:19](C)(C)[O:18]2)[C:3]=1C=O.C1N2[CH2:32][CH2:33]N(CC2)C1.Cl.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])C=C>>[OH:21][B:17]1[C:6]2[CH:7]=[C:8]([OH:10])[CH:9]=[C:2]([CH3:1])[C:3]=2[CH:19]([C:32](=[CH2:33])[C:35]([O:39][CH2:40][CH3:41])=[O:38])[O:18]1
Reactant: Cc1cc(OC2CCCCO2)cc(B2OC(C)(C)C(C)(C)O2)c1C=O
Reactant: C=CC(=O)OCC
Reactant: C1CN2CCN1CC2
Agent: Cl
Product: C=C(C(=O)OCC)C1OB(O)c2cc(O)cc(C)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Into a 50-mL round-bottom flask was placed a solution of 2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (5 g, 14.45 mmol, 1.00 equiv) in ethyl acrylate (10 mL), then added DABCO (2.42 g, 21.61 mmol, 1.50 equiv). The resulting solution was stirred for 24 h at room temperature. The pH value of the solution was adjusted to 3 with HCl (3N) and stirred for 2 h at 30° C. The resulting solution was extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with 2×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1). This resulted in 3.0 g (75%) of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acrylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6].N1C=CC=CC=1.[C:35](OC=O)(=[O:37])C>ClCCl>[CH:35]([NH:1][C:2]1([NH:7][C:8](=[O:28])[CH:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:5][NH:4][C:3]1=[O:6])=[O:37]
Reactant: NC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Reactant: CC(=O)OC=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CNC1(NC(=O)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)c2ccsc2)CNC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.3 %

Procedure:
The amine (42) (490 mg) in dry dichloromethane was cooled to 0° C. and treated with pyridine (211 mg) followed by formic-acetic anhydride (117 mg). The mixture was stirred at 0° C. for 5 minutes then allowed to warm to room temperature. After 1/2 hour the solvent was evaporated and the residue dried in vacuo. The solid was triturated with dry ether, filtered off, and washed with more ether before drying in vacuo to give the product (43) (510 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:23][N:24]([CH3:35])[C:25](=[O:34])[CH2:26][O:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][CH2:26][C:25]([N:24]([CH3:35])[CH3:23])=[O:34])[CH2:33][CH2:32]1)=[O:6]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CN(C)C(=O)COC1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Reaction time: 1 h
Yield: 61.1 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.2 g, 0.67 mmol), N,N-dimethyl-2-(piperidin-4-yloxy)acetamide (82) (0.125 g, 0.67 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.215 g, 0.67 mmol) were dissolved in DMF (10 mL), to this was added DIPEA (0.117 mL, 0.67 mmol) and the reaction was stirred for 1 hour. The solvent was evaporated to dryness and the gum was dissolved in acetonitrile (4 mL). The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a cream solid (0.191 g, 61.1% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.98-1.55 (4H, m), 2.96 (3H, s), 3.03 (3H, s), 3.17-3.06 (1H, m), 3.60-3.43 (2H, m), 3.72-3.67 (1H, m), 4.08-3.99 (1H, m), 4.19 (2H, q), 4.28 (2H, s), 7.01 (1H, t), 7.32-7.26 (2H, m), 7.78-7.70 (3H, m), 8.48-8.46 (1H, m), 10.89 (1H, s); m/z (LC-MS, ESI+), RT=1.55 (M+H 467).