Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].F[B-](F)(F)F.CN(C)C(O)=[N+](C)C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[C:51](=[N:59]O)([NH2:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>[Cl-].[Na+].O.CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@@H:11]([C:12]2[O:14][N:59]=[C:51]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[N:58]=2)[C@H:15]([OH:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: NC(=NO)c1ccccc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N[C@@H](c2nc(-c3ccccc3)no2)[C@@H](C)O)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 3.8 %

Procedure:
To a 25 mL round bottom flask charged with (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (413 mg, 1.5 mmol) (intermediate 3a) and anhydrous DMF (15 mL) was added O-(benztriazol-1-yl)N,N,N′,N′)-tetramethyluronium tetrafluorborate (743 mg, 2.3 mmol), diisopropylethylamine (1.3 mL, 7.5 mmol), and HOBt (42 mg, 0.31 mmol). This mixture was let stir for a period of 10 min, to this mixture was added benzamidoxime (312 mg, 2.3 mmol). This mixture was allowed to stir for a period of 16 h. The reaction was then heated to 100° C. for a period of 5 h then cooled to room temperature. To the reaction was added brine (25 mL) and this was extracted with EtOAc (2×25 mL). The combined organic extracts were then washed with water (20 mL) and brine (25 mL) then dried over sodium sulphate. Filtration and concentration gave a dark oil. This was purified via silica gel chromatography eluted with 50% EtOAc/hexanes. A second column was run, eluting with 30% EtOAc/hexanes to provide product (21 mg, 4%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.04 (m, 2H), 7.49 (m, 3H), 7.34 (d, J=8.6 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 5.40 (d, J=8.7 Hz, 1H), 4.87 (dd, J=3.9, 8.7 Hz, 1H), 4.42 (br s, 1H), 2.77 (br s, 1H), 2.33 (s, 3H), 1.33 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.IC>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a stirred solution of methyl 4-bromo-3-hydroxybenzoate (10.0 g) in DMF (50 mL) was added potassium carbonate (17.9 g) and iodomethane (9.2 mg). The mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum to give 10 g of the title compound, that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCC1CCC1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CCC2)cc1
Temperature: 100 °C

Procedure:
The mixture of 2.50 g (14.5 mmol) of 4-bromophenol, 2.44 ml (21.7 mmol) of bromomethylcyclobutane and 7.99 g (57.8 mmol) of K2CO3 in 3 ml DMF is stirred at 100° C. over night. The reaction mixture is extracted with water and EtOAc. The organic layer is dried, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[C:7]1=O)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCc2cc(OC)ccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(OC)ccc2C1
Reaction time: 72 h
Yield: 87.5 %

Procedure:
10% Pd/C (195 mg) was added to a suspension of 6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester (1.07 g, 4.32 mmol) and FeCl3, (5 mg) in EtOH (30 mL) under N2. The suspension was hydrogenated at 40 psi for 3 days. The suspension was filtered through a Celite pad and the filtrate was concentrated to a leave crude oil. The oil was purified using medium pressure chromatography on silica (CHCl3) to provide a colorless oil (886 mg, 88.3% yield). 1H-NMR (300 MHz, CDCl3) δ 1.28 (t, J=7.2 Hz, 3H). 1.84 (m, 1H), 2.19 (m, 1H), 2.70 (m, 1H), 2.83 (m, 2H), 2.93 (m, 2H), 3.77 (s, 3H), 4.17 (q, J=7.2 Hz, 2H), 6.62 (s, 1H), 6.69 (dd, J=8.4, 2.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]([OH:13])[C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Product: N[C@H](C(=O)O)C(O)c1ccccc1

Procedure:
In 10.0 mL of buffer was dissolved glycine (25.4 mg, 0.338 mmol) and benzaldehyde (35 μL, 0.344 mmol). This solution (100 μL) was added to 100 μL of the SHMT solution (0.1 mg enzyme). Aliquots were taken at incubation times of 1.0, 5.25, and 7.0 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.I[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.OC1C=CC=C2C=1N=CC=C2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[CH:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2nc[nH]n2)cc1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(Br)cc3)n2)cc1
Temperature: 150 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
In a 500 mL flask, 3-(4-bromophenyl)-1H-1,2,4-triazole (20.0 g, 89.6 mmol), 1-iodo-4-(trifluoromethoxy)benzene (39.0 g, 135 mmol) were diluted with N,N-dimethylformamide and water (4:1, 100 mL). Then copper(I) iodide (15.3 g, 80.6 mmol), 8-hydroxyquinoline (8.50 g, 58.2 mmol) and cesium carbonate (87.4 g, 269 mmol) were added. The reaction was heated to 150° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered through Celite®. Brine solution was added to the filtrate and stirred for 15 minutes. The layers were separated and the aqueous layer further extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash column chromatography using 15% ethyl acetate/petroleum ether as eluent to afford the title compound as a white solid (10.0 g, 29%): mp 100-103° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.07 (d, J=9.0 Hz, 2H), 8.05 (d, J=9.0 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H); ES+ m/z 385 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>ClCCl>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][Br:37])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl[3-(hydroxymethyl)phenyl]carbamate (0.90 g, 4.0 mmol) in dichloromethane (15 mL) cooled at 0° C. was added triphenylphosphine (1.59 g, 6.05 mmol) and carbon tetrabromide (2.01 g, 6.05 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 20% EtOAc/hexanes) to afford tert-butyl[3-(bromomethyl)phenyl]carbamate (0.82 g, 70%). LC-MS: (FA) ES+ 271.
Reaction SMILES: C1N2C3C(C=NC2=CN=C1)=CC=CC=3C(N)=O.Cl.C1(NCC2CCCCC2N)CC1.[CH:31]1([N:34]2[CH2:43][CH:42]3[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]3[C:44](=[O:73])[C:45]4[N:46]([CH:48]=[C:49]([C:61]([NH:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=5[F:72])=[O:62])[C:50](=[O:60])[C:51]=4[O:52]CC4C=CC=CC=4)[CH2:47][CH:35]23)[CH2:33][CH2:32]1>>[CH:31]1([N:34]2[CH2:43][CH:42]3[CH:37]([CH2:38][CH2:39][CH2:40][CH2:41]3)[N:36]3[C:44](=[O:73])[C:45]4[N:46]([CH:48]=[C:49]([C:61]([NH:63][CH2:64][C:65]5[CH:70]=[CH:69][C:68]([F:71])=[CH:67][C:66]=5[F:72])=[O:62])[C:50](=[O:60])[C:51]=4[OH:52])[CH2:47][CH:35]23)[CH2:33][CH2:32]1
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2
Agent: Cl
Agent: NC(=O)c1cccc2c1N1CC=NC=C1N=C2
Agent: NC1CCCCC1CNC1CC1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(C3CC3)C1C2

Procedure:
racemic-(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1∝,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide. In a manner similar to that described in example Z-35, from 16a (45 mg, 0.0957 mmol) and racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanamine hydrochloride (102 mg, 0.425 mmol) was prepared racemic 4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide as a white solid after silica gel chromatography (1-12% methanol/dichloromethane gradient elution). This material was deprotected in a second step similar to the procedure described in example Z-87. Thus, from racemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (56 mg, 0.0949 mmol) the title compound was prepared as a white solid (41 mg, 81%). 1H NMR (CDCl3) 12.10 (br s, <1H), 10.45 (m, 1H), 8.27 (s, 1H), 7.33 (m, 1H), 6.88 (m, 2H), 4.77 (m, 1H), 4.61-4.40 (m, 4H), 4.33 (m, 1H), 2.94 (m, 1H), 2.79 (m, 1H), 2.17 (m, 1H), 1.86-0.86 (m, 10H), 0.658 (m, 1H), 0.499-0.32 (m, 2H); ES+MS: 499 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1>CS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:27])[C:7]3[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([Cl:25])[CH:18]=4)[N:13]=[C:12]([OH:26])[C:8]=3[NH:9][C:10]=2[CH:11]=1
Reactant: COc1ccc(-n2nc(O)c3[nH]c4cc(Cl)ccc4c(=O)c3c2=O)cc1Cl
Agent: CS(=O)(=O)O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(-c3ccc(O)c(Cl)c3)c(=O)c12
Temperature: 145 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
7-Chloro-2-(3-chloro-4-methoxyphenyl)-4-hydroxy-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (previously prepared in Example 37 1.00 g, 2.47 mM) was stirred in methanesulfonic acid (20 mL) to give a black solution. This solution was heated to 145° C. for 6 hours and cooled to room temperature. Vater (60 mL) was added to give a tan suspension which was stirred for 3 hours and filtered. The collected solids were washed with water and ether to give the title compound as a gold powder (0.98 g, 76 %), mp 350-353° C.; MS(CI): 390.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:11][CH2:12][N:13]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:14][CH2:15]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 97.4 %

Procedure:
To a 500 mL round-bottomed flask equipped with magnetic stirring was added 1-(2-nitrophenyl)piperazine (Emka-Chemie) (30 g, 145 mmol) in CH2Cl2 (300 mL). A solution of Na2CO3 in H2O (61.2 g in 100 mL) was added, and the reaction mixture was stirred for 5 min. Stirring was stopped, benzyl bromide (18.6 mL, 159 mmol) was added, and the reaction was heated at reflux for 4 h. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford 1-(2-nitrophenyl)-4-benzylpiperazine as an orange oil (42 g). MS (ESI, pos. Ion) m/z: 298 (M+H); MS (ESI, neg. Ion) m/z: 296 (M−H). Calc'd for C17H19N3O2: 297.15.
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:9]([F:20])=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][N:7]2[CH:21]1[CH2:23][CH2:22]1.C([Sn](C#[C:44][Si:45](C)([CH3:47])[CH3:46])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH:21]1([N:7]2[C:8]3[C:3](=[C:2]([Si:45]([CH3:47])([CH3:46])[CH3:44])[C:11]([F:12])=[C:10]([N:13]4[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]4)[C:9]=3[F:20])[C:4](=[O:29])[C:5]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6]2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c(Br)c2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCN(C)CC3)c(F)c([Si](C)(C)C)c2c1=O
Yield: 58.1 %

Procedure:
1.1 g of ethyl 5-bromo-1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylate, 1.2 g of tributylstannyl-trimethylsilylacetylene and 0.135 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 3 hours in 10 ml of absolute toluene. The reaction mixture is treated with a further 5 ml of toluene and filtered while hot. The product crystallizes out of the filtrate. After filtration with suction and drying, 0.63 g of the title compound is obtained (56% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.21 g, 6.99 mmol) and Et3N (0.85 g, 1.2 mL, 8.4 mmol) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (0.88 g, 0.60 mL, 7.7 mmol). After 1 h, brine was added and the reaction extracted with CH2Cl2 (2×). The combined organics were dried to give 1.65 g (94%) of 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester a yellow solid that was used without further purification. 1H NMR (CDCl3): 5.20 (tt, J=6.7, 4.2 Hz, 1H), 4.28 (ddd, J=10.3, 6.7, 1.2 Hz, 2H), 4.10 (ddd, J=10.4, 4.2, 1.1 Hz, 2H), 3.07 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 0.1 %

Procedure:
To a solution of 1-t-butoxycarbonyl-3-hydroxyazetidine (3.24 g, 18.7 mmol) (obtained as described in Reference Example 31(1)) in methylene chloride (160 ml) were added methanesulfonyl chloride (1.59 ml, 20.6 mmol) and triethylamine (2.89 ml, 20.6 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1→1:2) as the eluant to afford 1-t-butoxycarbonyl-3-(methanesulfonyloxy)azetidine (4.71 mg, yield 100%) as a pale yellow oil.
Reaction SMILES: CN(C)CCCN=C=NCC.[NH2:12][CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1>C1COCC1.C(OCC)(=O)C>[CH3:22][O:23][C:24](=[O:34])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](=[O:32])[NH:12][CH2:13][CH:14]([OH:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: NCC(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCC(=O)NCC(O)c1ccccc1
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (8.5 g, 44.3 mL) to a solution of 2-amino-1-phenylethanol (5.0 g, 36.4 mmol), suberic acid monomethyl ester (6.85 g, 36.4 mmol) and 1-hydroxybenzotriazole (HOBt, 5.0 g, 37.0 mmol) in THF (200 mL) at room temperature under nitrogen. Stir the mixture for 12 hours. Dilute the mixture with ethyl acetate (600 mL), wash with 1N HCl (2×150 mL), brine (2×150 mL), NaHCO3 (2×150 mL) and brine (150 mL) solutions and dry over sodium sulfate. Remove the solvent under reduced pressure to provide 7-(2-hydroxy-2-phenylethylcarbamoyl)heptanoic acid methyl ester (10.3 g, 91%), which is used in the following step without purification.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:16][C:17]1[N:22]=[C:21](F)[C:20]([F:24])=[CH:19][N:18]=1.CCOC(C)=O.CCCCCCC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[C:20]([F:24])=[CH:21][N:22]=[C:17]([F:16])[N:18]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ncc(F)c(F)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1nc(F)ncc1F
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 68.1 %

Procedure:
To a solution of (R)-4-((R)-1-(tert-butoxy)ethyl)oxazolidin-2-one (6.35 g, 33.9 mmol) in DMF (170 mL) under a nitrogen atmosphere at 0° C. was added sodium hydride (2.14 g, 50.9 mmol, 60%) portion wise over 3 minutes. The reaction mixture was then stirred for 2 hr at 0° C. whereupon 2,4,5-Trifluoropyrimidine (5 g, 37.3 mmol) was added and the reaction mixture allowed to stir 75 minutes at 0° C. then the mixture was allowed to warm to RT and stirred for 1 hr at RT. The reaction mixture was quenched with the slow addition of saturated solution of NH4Cl and the aqueous mixture extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 50%) provided a colorless oil of (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,5-difluoropyrimidin-4-yl)oxazolidin-2-one (6.97 g, 23.1 mmol, 68% yield) which crystallizes upon standing. 1H NMR (400 MHz, CDCl3) 1.10 (d, J=6.26 Hz, 3H) 1.18 (s, 9H) 4.25-4.35 (m, 1H) 4.49-4.62 (m, 2H) 4.65-4.73 (m, 1H) 8.45 (d, J=1.57 Hz, 1H). LCMS m/z 246.1 (-t-butyl fragment) (M+H)+, Rt 0.91 min.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[C:3]=1[C:8]([O:10]CC)=O.C([O-])=O.[NH4+].[CH:17]([NH2:19])=O>C1(C)C=CC=CC=1>[CH3:7][C@H:4]1[C:3]2[C:8]([OH:10])=[N:19][CH:17]=[N:1][C:2]=2[CH2:6][CH2:5]1
Reactant: NC=O
Reactant: CCOC(=O)C1=C(N)CC[C@H]1C
Agent: O=C[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CCc2ncnc(O)c21
Temperature: 150 °C
Reaction time: 36 h

Procedure:
A 2 L 3-neck round bottom flask equipped with a condenser, internal temperature probe, was charged with (R)-ethyl 2-amino-5-methylcyclopent-1-enecarboxylate (185 g, 1093 mmol) and ammonium formate (103.4 g, 1640 mmol) in formamide (400 mL) and toluene (200 mL). The reaction was heated to an internal temperature of 150° C. and stirred for 36 hours. The reaction was cooled and transferred to a 2 L single next flask and excess formamide was removed by high vacuum distillation. The resulting oil was dissolved in CH2Cl2 and washed with brine. The combined aqueous layers were extracted with CH2Cl2. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude product as a brown semi solid which was taken into the next step without any further purification.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.[Br:27][C:28]([CH2:30]Br)=[CH2:29]>C1COCC1>[Br:27][C:28](=[CH2:29])[CH2:30][C:12]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10][N:9]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1
Reactant: C=C(Br)CBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(Br)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
Lithium diisopropylamide (29.1 mL, 58.3 mmol) was added dropwise at −78° C. To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (9.56 mL, 38.9 mmol) in THF (200 mL), and stirred at this temperature for 50 min. 2,3-Dibromoprop-1-ene (5.47 mL, 56.0 mmol) in THF (10 mL) was added to the reaction mixture slowly and the resulting mixture was stirred for 1.5 hr at −78° C. The reaction mixture was quenched with NH4Cl solution (15 mL) and was allowed to warm to room temperature and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organics were washed with brine (30 mL), dried over MgSO4 and concentrated to get the crude product which was purified by silica gel column chromatography (RediSep 220 g Gold column) using (0-30) % EtOAc/Hexanes as mobile phase to give the title compound.