Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[O:33][CH2:34]SC)(C(C)(C)C)(C)C.C1CCCCC=1.S(Cl)(Cl)(=O)=O.N#N.[N-:50]=[N+:51]=[N-:52].[Na+]>C(Cl)Cl>[N:50]([CH2:34][O:33][C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([C:23]#[C:24][CH2:25][NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12]1)=[N+:51]=[N-:52]
Reactant: [N-]=[N+]=[N-]
Reactant: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: N#N
Agent: [Na+]
Solvent: C1=CCCCC1
Solvent: ClCCl
Solvent: O=S(=O)(Cl)Cl
Product: [N-]=[N+]=NCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
To a solution of (3) (348 mg, 0.63 mmol) and cyclohexene (0.32 ml, 3.2 mmol) in dry CH2Cl2 (5 ml) at 4° C., sulfurylchoride (1M in CH2Cl2, 0.76 ml, 0.76 mmol) was added drop wise under N2. After 10 min TLC indicated the full consumption of the nucleoside (3). The solvent was evaporated and the residue was subjected to high vacuum for 20 min. It was then redissolved in dry DMF (3 ml) and treated with NaN3 (205 mg, 3.15 mmol). The resulting suspension was stirred under room temperature for 2 h. The reaction was quenched with CH2Cl2 and the organic layers were washed with sat aq. NaCl solution. After removing the solvent, the resulting yellow gum was redissolved in THF (2 ml) and treated with TBAF (1 M in THF, 0.5 ml) at room temperature for 30 min. The solvent was removed and the reaction worked up with CH2Cl2 and sat. aq. NaHCO3 solution. The aqueous layer was extracted three times with CH2Cl2. Purification by chromatography on silica (EtOAc:petroleum ether 1:1 to EtOAc) gave (4) (100 mg, 37%) as a pale yellow foam. 1H NMR (d6 DMSO) δ 2.15-2.26 (m, 2H, H-2′), 3.47-3.57 (m, 2H, H-5′), 3.88-3.90 (m, 1H, H-4′), 4.14 (d, J=4.7 Hz, 2H, CH2NH), 4.24-4.27 (m, 1H, H-3′), 4.75 (s, 2H, CH2N3), 5.14 (t, J=5.2 Hz, 1H, OH), 5.96-6.00 (m, 1H, H-1′), 8.10 (s, 1H, H-6), 10.00 (s, 1H, NHCOCF3)), 11.26 (s, 1H, NH).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:28]=[CH:27][C:19]3[C:20](=O)[O:21]C(C)(C)[O:23][C:18]=3[CH:17]=2)=[C:11]([F:29])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:36]>C(O)(C)C>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:28]=[CH:27][C:19]([C:20](=[O:21])[NH2:36])=[C:18]([OH:23])[CH:17]=2)=[C:11]([F:29])[CH:10]=1)[CH2:30][CH2:31][CH:32]1[CH2:34][CH2:33]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCC1CC1)Cc1ccc(Oc2ccc3c(c2)OC(C)(C)OC3=O)c(F)c1
Reactant: N
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N(CCC1CC1)Cc1ccc(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2-Cyclopropyl-ethyl)-[4-(2,2-dimethyl-4-oxo-4H-benzo[1,3]dioxin-7-yloxy)-3-fluoro-benzyl]-carbamic acid tert-butyl ester (I-1d-2: 15.8 g) was dissolved in 35 mL of a 2 M solution of ammonia in isopropanol. The resulting solution was then treated with 50 mL of a saturated aqueous ammonia solution and the resulting mixture heated at 80° C. After 8 hours, the reaction mixture was cooled to ambient temperature and concentrated with a rotary evaporator. The residue was diluted with ethyl acetate and the organic solution was washed twice with water, once with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50% ethyl acetate in heptane to afford the title compound (I-1e-2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[CH3:22][N:23]([CH2:25][CH2:26]Cl)[CH3:24].Cl>O1CCOCC1.C(O)C>[CH3:22][N:23]([CH2:25][CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:9]=1)[CH3:24]
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)CCOc1ccccc1-c1nc(-c2ccccc2)no1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% sodium hydride suspension in oil for 15 minutes at 25-30° C. To this solution is added 60 ml of anhydrous dioxane, the resulting mixture is combined with 2.88 g of 2-(N,N-dimethylamino)ethylchloride hydrochloride and 0.6 g of 80% sodium hydride suspension in oil. This solution is also stirred for 15 minutes at 25-30° C. The combined solutions are refluxed for 8 hours, left to stand overnight and evaporated down in vacuo. The residue is mixed with water and 20 ml of 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent evaporated in vacuo and the residue chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 2.5% of a 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 2.2 g (64% of theory). m.p.: 186-187° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CS(C)=O.Br[C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]>[F:27][C:25]1[CH:24]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: COC(=O)c1ccc(F)cc1Br
Agent: [Cu]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1-c1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 2 h
Yield: 113.3 %

Procedure:
To 2-bromo-4-fluoro-1-nitrobenzene (185.16 mg, 0.842 mmol) was added Pd2dba3 (23.12 mg, 0.025 mmol) and copper powder (271 mg, 4.26 mmol). Dimethylsulfoxide (2.3 ml) and methyl 2-bromo-4-fluorobenzoate (0.122 ml, 0.842 mmol) were added and the mixture was stirred vigorously at 100° C. for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and dried (anhydrous Na2SO4) and concentrated to give a yellow oil (279.8 mg). This oil was utilized without purification for the preparation of Example 38b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][N:27]=[C:28]([CH2:41][CH3:42])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)([CH3:25])([CH3:24])[CH3:23].Cl>CN(C)C=O>[C:22]([O:26][N:27]=[C:28]([CH2:41][CH3:42])[CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:15][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])=[CH:5][C:4]=1[Cl:14])([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCC(COCCCCCOS(C)(=O)=O)=NOC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOC(C)(C)C
Reaction time: 24 h
Yield: 83.8 %

Procedure:
First, 0.46 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.25 g of potassium carbonate, 0.58 g of 1-(5-(methanesulfonyloxy)pentyloxy)-2-butanone O-tert-butyloxime, and 15 ml of N,N-dimethylformamide are placed in a reaction vessel. After stirring at 55° C. to 60° C. for 24 hours, the reaction mixture is poured into diluted hydrochloric acid, and extracted twice with ethyl acetate. The ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 0.69 g (yield, 84%) of 1-(5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxy)-2-butanone O-tert-butyloxime, nD23.4 1.5140.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[N+](=[CH2:23])=[N-]>C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]([OH:14])[C:11]([O:13][CH3:23])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)[C@@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.00 g (3.8 mmole) of 3(S)-t-butoxycarbonylamino-2-hydroxy-5-methylhexanoic acid prepared by the method of R. L. Johnson [J. Med. Chem., 25, 605 (1982)] in 30 ml, of methanol was stirred, whilst cooling with ice, and then a diethyl ether solution of diazomethane was added and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off and the resulting solid was recrystallized from hexane to give 952 mg of the title product as colorless needles, melting at 84°-85° C.; [α]25 -10.2° (C=1.26, methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Br[CH2:14][C:15]1[CH:19]=[C:18]([C:20]2[S:21][C:22]([Cl:25])=[CH:23][CH:24]=2)[O:17][N:16]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[C:8]([I:12])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(I)nc1C
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc(I)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 500 mg 2-Iodo-5-methyl-3H-imidazole-4-carboxylic acid ethyl ester in 2 ml DMF 1.1 g caesium carbonate and 547 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001), 460 pp. WO 0107436 A2] were added and the mixture was stirred for 2 h at RT. After addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 630 mg.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1.[OH:28][CH2:29][C@H:30]1[O:35][CH2:34][CH2:33][N:32]([C:36]2[S:37][CH2:38][C:39](=[O:41])[N:40]=2)[CH2:31]1>>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:38]3[S:37][C:36]([N:32]4[CH2:33][CH2:34][O:35][C@H:30]([CH2:29][OH:28])[CH2:31]4)=[N:40][C:39]3=[O:41])=[CH:12][CH:13]=2)[C:8]([Cl:17])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(c1)c(Cl)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazol-5-ylmethylene]-2-(2-(S)-hydroxymethyl-morpholin-4-yl)-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-chloro-1H-indazole-5-carbaldehyde and 2-(2-(S)—Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following general procedure D.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH:15]=O)[CH:6]=1)=[O:4].[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CC(O)=O.C([BH3-])#N.[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:17][CH3:18])[C:11]=2[CH2:15][NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][C:20]([F:19])([F:30])[F:31])=[CH:23][CH:24]=2)[CH:6]=1)=[O:4]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc2c(C=O)c(OC)ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc2c(CNCc3ccc(OC(F)(F)F)cc3)c(OC)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
To a stirred solution of 6-methoxy-5-formyl-2-naphthoic acid methyl ester (1.09 g, 4.46 mmol) in EtOH (40 mL) at room temperature was added 4-trifluoromethoxy-benzyl amine (0.749 mL, 4.91 mmol) followed by HOAc (0.255 mL, 4.46 mmol). After 10 min. at this temperature, sodium cyanoborohydride (0.420 g, 6.69 mmol) was added, and reaction was continued stirring at rt for 4 h. After 1 h at this temperature, the reaction was heated to 45° C. for 2 h. The solution was quenched with sat. aq. NaHCO3 (20 mL) and then extracted with EtOAc (200 mL). The organic layer was washed with brine (20 mL) and dried (MgSO4). After concentration, the residue was purified by flash chromatography (0 to 10% MeOH:CHCl3 gradient) to afford the product (0.780 g, 42%) as a solid; 1H NMR (DMSO-d6) δ3.77 (s, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 4.07 (s, 2H), 7.26 (d, J =8.0 Hz, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.48 (d, J=9.2 Hz, 1H), 7.88 (dd, J=1.9, 8.9 Hz, 1H), 8.06 (d, J=5.2 Hz, 1H), 8.08 (d, J=5.3 Hz, 1H), 8.52 (d, J=1.7 Hz, 1H); mass spectrum [(+) El], m/z 420 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31].CN1CCCC1.N1C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:16]=3[CH3:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: NCCCO
Reactant: Cc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Agent: CN1CCCC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1c(NCCCO)c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Temperature: 70 °C
Reaction time: 15 h
Yield: 26.9 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-methyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (500 mg), 3-amino-1-propanol (400 mg) and N-methylpyrrolidine (170 mg) were added to pyridine (1,500 mg), and the mixture was stirred at 70° C. for 15 hours. Since the raw material were not dissolved, N,N-dimethylformamide (1 ml) was added to the mixture, followed by stirring at 70° C. for 43 hours. The reaction mixture was concentrated under reduced pressure. A process of adding distilled water (1 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Another process of adding toluene (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. A further process of adding ethanol (1.5 ml) to the resultant residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Ethanol (1 ml) was added to the resultant residue, and the mixture was heated under reflux for 5 minutes and allowed to cool. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (155 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:7](Cl)(=[O:11])[C:8]([Cl:10])=[O:9]>>[C:8]([Cl:10])(=[O:9])[C:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)CO
Product: CC(C)(C)COC(=O)C(=O)Cl
Yield: 92.7 %

Procedure:
In this example the product was prepared in two synthetic steps. In the first step neopentyl alcohol was reacted with 50% molar excess of oxalyl chloride. Upon completion of the reaction the excess oxalyl chloride was stripped from the product at reduced pressure to produce neopentyl chlorooxalate having an assay of 100% and in a corrected yield of 92.7%. In the second step neopentyl chlorooxalate was reacted with 2,5-dimethyl-2,5-dihydroperoxyhexane, in the presence of pyridine, to yield the product as described below:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][C:12]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:17]([C:12]3([CH3:11])[CH2:16][CH2:15][CH2:14][CH2:13]3)=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: CC1(C(=O)Cl)CCCC1
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCC1

Procedure:
(2-Bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cyclopentyl)-methanone was prepared starting from 2-bromo-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-cyclopentanecarbonyl chloride following general procedures as described in these Examples. MP 206.9-207.9° C., M+H=308.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(O)C>ClCCl>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1

Procedure:
2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (3.10 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.50.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[CH3:31][C@@H:32]1[CH2:37][CH2:36][C@H:35](O)[CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.C1COCC1>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C@H:35]4[CH2:36][CH2:37][C@H:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:20][CH:19]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1
Reactant: C[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O)cc3)n2)C2CCCC2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN(c2nccc(-c3ccc(O[C@H]4CC[C@H](C)CC4)cc3)n2)C2CCCC2)c1
Temperature: 25 °C

Procedure:
To a THF (2 mL) solution of 3-({cyclopentyl-[4-(4-hydroxy-phenyl)-pyrimidin-2-yl]-amino}-methyl)-benzoic acid methyl ester (39 mg, 0.10 mmol) (prepared in Example 172) was added cis-4-methyl-cyclohexanol (11 mg, 0.10 mmol) and triphenylphosphine (25 mg, 0.10 mmol). After the mixture was cooled 5 min. in an ice bath, diisopropyl azodicarboxylate (DIAD, 19.1 μL, 0.10 mmol) was added. The solution was stirred at room temperature until complete. Water was added, and the mixture was extracted with ethyl acetate (3×2 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated. Purification was carried out by silica gel chromatography eluting with hexanes/ethyl acetate 9:1 then 4:1 to give 16 mg of 3-[(cyclopentyl-{4-[4-(trans-4-methyl-cyclohexyloxy)-phenyl]-pyrimidin-2-yl}-amino)-methyl]-benzoic acid methyl ester. LCMS m/z: 501 (M+1)+.
Reaction SMILES: [CH:1](=[N:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.II.C(OO)(=O)C>ClCCCl>[C:2]1([CH:1]=[N+:8]=[N-:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=Cc1ccccc1
Agent: CC(=O)OO
Agent: CN(C)C(=N)N(C)C
Agent: II
Solvent: ClCCCl
Product: [N-]=[N+]=Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To benzaldehyde hydrazone (5.95 g, 0.05 moles) in 1,2-dichloroethane (50 ml) containing 1,1,3,3-tetramethylguanidine (26.4 ml) and iodine (2 ml, 1% w/v solution) was added peracetic acid solution (11.4 ml, 1.27 × 0.05 moles) over 12 minutes at 0°. The red solution, which was gently evolving nitrogen, was stirred for 20 minutes at 0° to -5° before being washed with water (5 × 250 ml) and made up to 250 ml in a volumetric flask. An aliquot (50 ml) treated with excess acetic acid yielded 199 ml gas at NTP which corresponded to a yield of diazoalkane of 88.9%.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O.C(N(CC)CC)C>[NH:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][C:31]([NH:1][C@H:2]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])=[O:32]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of 20.35 g of H-Lys(Z)-OBzl.HCl (manufactured by Kokusan Kagaku) in 35 ml of dimethylformamide (called DMF hereinbelow), after neutralized by addition under cooling with ice of 7 ml of triethylamine, were added 8.76 g of Boc-Gly-OH (manufactured by Kokusan Kagaku), 7.43 g of HOBt (manufactured by Kokusan Kagaku) and 11.35 g of DCC (manufactured by Kokusan Kagaku). The mixture was stirred for 3 hours and at 4° C. for additional 16 hours. Dicyclohexylurea by-product was removed by filtration followed by addition of 300 ml of ethyl acetate. The resulting mixture was washed successively with saturated aqueous sodium chloride, 8% by weight aqueous sodium carbonate, saturated aqueous sodium chloride, 8% by weight aqueous citric acid and saturated aqueous sodium chloride. From the ethyl acetate layer, after dried over anhydrous sodium sulfate, was removed the solvent, and the residue was again dissolved in a small amount of ethyl acetate. From the solution after filtered, the solvent was completely distilled off to give 21.1 g (80% yield) of Boc-Gly-Lys(Z)-OBzl as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][N:12]([C:16](=[O:26])[CH2:17][O:18]CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([N:27]2[CH2:31][C@H:30]([CH2:32][NH:33][C:34](=[O:36])[CH3:35])[O:29][C:28]2=[O:37])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:15][C@@H:14]2[C@@H:10]([CH2:11][N:12]([C:16](=[O:26])[CH2:17][OH:18])[CH2:13]2)[CH2:9]1
Reactant: [H][H]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)COCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)CO)C[C@H]4C3)c(F)c2)C(=O)O1

Procedure:
The (S)-N-[[3-[3-fluoro-4-[cis-3-(benzyloxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (110 mg, 0.22 mmol), methanol (25 mL) and 10% palladium on carbon (100 mg) are combined and placed under 40 p.s.i. of hydrogen and shaken for 5 days. The reaction is filtered through celite, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 100 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.20, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, mp 167-168° C.