Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[N:6]=1.[NH2:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17]>C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:14][C@H:15]([CH2:18][CH2:19][CH3:20])[CH2:16][OH:17])[S:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: CCC[C@@H](N)CO
Reactant: Brc1ccc(-c2csc(Br)n2)cc1
Solvent: ClCCl
Product: CCC[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Temperature: 150 °C
Reaction time: 18 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromo-4-(4-bromophenyl)-1,3-thiazole (2.9 g, 9.09 mmol), prepared in step 2 of Example 1, and (R)-(−)-2-amino-pentanol (2.82 g, 27.2 mmol) was stirred under nitrogen at 150° C. for 18 h. After cooling to room temperature, the residue was taken up in methylene chloride, applied to a Biotage FLASH 40+™ cartridge and the methylene chloride allowed to evaporate. Purification of the residue on the samplet on a Horizon™ Flash Collector (the Biotage FLASH 40+™ cartridge) using a linear gradient of 5% ethyl acetate-hexane to 100% ethyl acetate gave (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}pentan-1-ol (2.56 g, 83%) as a yellow solid, mp 63-65° C.; MS (ESI) m/z 341 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[CH3:31][Mg]Cl.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][CH:11]([CH:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH:14]([OH:15])[CH3:31])[CH2:10]2)=[CH:29][CH:28]=1
Reactant: O=CC(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: C[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 790 mg (1.77 mmol) of {1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}(3,5-difluorophenyl)acetaldehyde in 20 mL of THF was added slowly a solution of 1.18 mL (3.54 mmol) of methylmagnesium chloride (3.0M solution in THF) at −78° C. and stirred for 1 h. The reaction mixture was warmed to 0° C. for 1 h and 3 g of sodium sulfate decahydrate was added to quench the reaction, followed by stirring for 1 h at rt. The reaction mixture was filtered and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone=8:1 to afford the title compound. 1NMR(CDCl3) δ 0.94 (d, J=6.7 Hz, 3H), 3.44 (d, J=6.5 Hz, 1H), 3.77 (m, 1H), 3.97 (s, 2H), 4.02 (s, 2H), 4.34 (m, 1H), 4.53 (s, 1H), 6.69 (m, 1H), 6.78 (m, 2H), 7.28 (d, J=8.5 Hz, 4H), 7.38 (d, J=8.5 Hz, 4H); Mass Spectrum: m/e=462 (M+1 35Cl, 35Cl) and 464 (M+1 35Cl, 37Cl).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH:6](=O)[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>O>[CH:6](=[N:1][NH:2][C:3]([NH2:5])=[S:4])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNC(N)=S
Reactant: O=CC=Cc1ccccc1
Solvent: O
Solvent: CCO
Product: NC(=S)NN=CC=Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of 18.2 g (0.20 m) of thiosemicarbazide in 250 ml of hot water was gradually added to a solution of 26.4 g (0.20 m) of cinnamaldehyde in 250 ml of hot 2B ethanol. Small, colorless crystals began to ppt from the homogeneous mixture after several minutes of heating on a steam bath. Heating was continued for a half an hour, after which the mixture was cooled to room temperature and the product was collected by filtration, washed with cold ethanol, and air-dried to yield 25.5 g of small, pale yellow crystals. An additional 18.3 g of product was recovered by concentrating the mother liquors. Recrystallization from ethanol gave 29.3 g (0.14 m) of small, pale yellow crystals, m.p. 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CS(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: Nc1cccc(N)n1
Solvent: CS(C)=O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)n1
Temperature: 80 °C
Yield: 19.7 %

Procedure:
2,6-Diaminopyridine (9.2 mmol, 1.0 g) and 2-fluoro-5-nitropyridine (4.6 mmol, 0.65 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 h. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N2-(5-nitropyridin-2-yl)pyridine-2,6-diamine as a reddish crystalline solid (0.21 g, 20% yield): 1H NMR (500 MHz, CDCl3) δ 9.13 (d, 1H, J=3.0 Hz), 8.36 (dd, 1H, J=3.0 Hz, J2=9.5 Hz), 7.94 (d, 1H, J=9.5 Hz), 7.66 (s, 1H), 7.46 (t, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0 Hz), 6.23 (d, 1H, J=8.0 Hz), 4.46 (s, 2H); Ms m/z (relative intensity) 232 (M+1, 100), 186 (57). The nitro compound (0.78 mmol, 0.18 g) and 10% Pd/C (20 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and was then filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (4 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:18][NH:19][CH3:20]>C1COCC1>[CH3:18][N:19]([CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9](=[O:11])[CH3:10])[S:6][CH:7]=1)[CH3:20]
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: CNC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CN(C)C)cs1
Temperature: 50 °C

Procedure:
Dissolved N-(4-chloromethyl-thiazol-2-yl)-acetamide (250 mg, 1.31 mmol) in 5 mL of THF. To this was added Na2CO3 (250 mg). Bubbled dimethyl amine in for 15 min. Sealed the flask and heated at 50° C. for 2 h. LC-MS analysis indicated the desired adduct. Filtered the mixture through diatomaceous earth and washed plug with 2×10 mL of THF. Concentrated to dryness to give 274 mg of N-(4-dimethylaminomethyl-thiazol-2-yl)-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:55])[CH2:47][CH2:46][CH2:45][N:44]([CH2:48][C@@H:49]([NH:53][CH3:54])[CH:50]([CH3:52])[CH3:51])[CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:53]([C@@H:49]([CH:50]([CH3:52])[CH3:51])[CH2:48][N:44]1[CH2:45][CH2:46][CH2:47][C:42]([F:55])([F:41])[CH2:43]1)[CH3:54])=[O:7]
Reactant: CN[C@H](CN1CCCC(F)(F)C1)C(C)C
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](CN1CCCC(F)(F)C1)N(C)C(=O)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 47.2 %

Procedure:
3-Chloro-4-fluorobenzoic acid (0.087 g, 0.50 mmol), TBTU (0.175 g, 0.54 mmol) and NMM (0.125 mL, 1.13 mmol) was mixed in DMF (2 mL). After 10 min at rt was (S)-1-(3,3-difluoropiperidin-1-yl)-N,3-dimethylbutan-2-amine (Compound S2) (0.1 g, 0.45 mmol) and additional DMF (1 mL) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (80 mg, 47%). HRMS (M+H)+: calculated 377.1607. found 377.1613.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=[O:4].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:18]1[CH2:17][C@H:16]([CH3:20])[NH:15][C@H:14]([CH3:13])[CH2:19]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: O=C(CCl)Nc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1

Procedure:
The product of step (i) (5.9 g) was dissolved in ethanol (50 ml) and cis-2,6-dimethylpiperazine (3 g) and sodium hydrogencarbonate (6.63 g) were added at room temperature under a nitrogen atmosphere. The mixture was heated under reflux for 24 hours and the cooled solution was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in 1M HCl (22 ml) and washed with dichloromethane. The aqueous solution was then basified to pH13 with a solution of sodium hydroxide and the product was extracted with dichloromethane. The organic layer was washed with water, brine, collected, dried (MgSO4) and concentrated under reduced pressure to give the subtitle compound as a beige solid. Yield 4 g.
Reaction SMILES: [N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[C:9]([N+:17]([O-:19])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.CC(O)C.Cl.[H][H]>CO>[N:1]1([CH:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[C:14]([CH3:15])[N:17]([OH:19])[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2ccc(C(c3ccccc3)n3ccnc3)cc2n1O
Yield: 40.6 %

Procedure:
A mixture of 4.9 parts of N-[4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrophenyl]acetamide, 12 parts of 2-propanol, saturated with hydrogen chloride and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of platinium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in dichloromethane and water and then the solution was neutralized with an ammonium hydroxide solution. The dichloromethane layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 2.2 parts (40.6%) of 6-[(1H-imidazol-1-yl)phenylmethyl]-2-methyl-1H-benzimidazol-1-ol as a residue (compound 219).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Li])CCC.[O:14]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([OH:14])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
To a stirred solution of 1-bromo-4-iodobenzene (93.7 g, 331.21 mmol, 1.10 equiv) in tetrahydrofuran (800 mL) under nitrogen at −78° C. was added dropwise of a solution of butyllithium (150 mL, 2.43 M in THF, 1.05 equiv) during 30 min. The resulting solution was stirred for 2 h at −78° C. To this was then added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (60 g, 301.13 mmol, 1.00 equiv) in tetrahydrofuran (800 mL) dropwise with stirring at −78° C. during 30 min. After stirring for 1 h at −78° C., reaction was carefully quenched with 350 mL of H2O. The resulting mixture was extracted with 2×400 mL of ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:200-1:10) as eluent to yield 91 g (85%) of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6]([OH:18])(C)[C:5](O)([CH3:19])[C:4]=2[CH:3]=1.F[C:22](F)(F)C(O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Br:16])=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]([CH3:19])([CH3:22])[C:4]=2[CH:3]=1
Reactant: CC1(O)c2cc(Br)ccc2-c2ccc(Br)cc2C1(C)O
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC1(C)C(=O)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
132.8 g (294 mmol) of 2,7-dibromo-9,10-dihydroxy-9,10-dimethyl-9,10-dihydrophenanthrene were suspended in 420 ml of acetic acid and 210 ml of trifluoroacetic acid under argon, and the mixture was stirred for 3 h under reflux. After the mixture had been stirred overnight at room temperature, it was filtered with suction, the residue was washed with water and methanol and dissolved in toluene, the solution was filtered through silica gel, and the solvent was removed, giving 89.9 g (80.4% of theory) of the product, which was used without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[C:17]2=[O:22])=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: Fc1cccc(CBr)c1
Product: Cc1nc(N2CCCC(Cc3cccc(F)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-3-fluorobenzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 89% yield: mp 170-171° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.39-7.17 (m, 6H), 6.99-6.89 (m, 3H), 6.01 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.33-4.21 (m, 1H), 3.99-3.89 (m, 1H), 3.45-3.36 (m, 1H), 3.86-3.27 (m, 2H), 2.63 (s, 3H), 2.10-1.96 (m, 1H), 1.94-1.73 (m, 2H), 1.61-1.43 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 171.8, 162.9, 162.6, 156.9, 152.1, 141.6, 137.9, 130.1, 128.8, 127.9, 127.7, 124.9, 119.5, 114.9, 114.6, 113.6, 48.0, 44.0, 37.3, 24.9, 21.3, 17.4; MS (ES+) m/z 438.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:21](=[O:22])[C:20]5=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]5[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:21]([OH:22])[C:20]5[C:19](=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a suspension of N-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]phthalimide (7.8 g, 19.8 mmol) in methanol (250 ml) and DCM (30 ml) was added NaBH4 (1.7 g, 45.5 mmol) at room temperature under nitrogen. After stirring for 0.5 hours the homogeneous reaction mixture was concentrated. The remaining solid was purified on a flash chromatography column (SiO2, 1:1 EtOAc/DCM, increased to 10% MeOH) to give 7.0 g (90%) of the desired product as a solid which was recrystallized from EtOAc, m.p.=172°-173° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([F:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.[Br:12]N1C(=O)CCC1=O.BrBr>O>[Br:12][CH:10]([C:4]1[N:3]=[C:2]([Cl:1])[N:7]=[C:6]([Cl:8])[C:5]=1[F:9])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nc(Cl)nc(Cl)c1F
Agent: BrBr
Solvent: O
Product: CC(Br)c1nc(Cl)nc(Cl)c1F
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of the compound of part (i) (400 g), N-bromosuccinimide (730 g), azoisobutyronitrile (33.7 g), bromine (65.5 g) and water (6.4 L) was heated at 80–85° C. for 5 hours. Further N-bromosuccinimide (183 g) was added, heating continued for 2 hours then further azoisobutyronitrile (33.7 g) added. After heating for 2 hours at 85° C. further azoisobutyronitrile (33.7 g) was added and heating continued for 3 hours. The reaction was cooled, diluted with water (4 L) and extracted with dichloromethane (2×3 L). The combined organic extracts were washed with a solution of sodium metabisulphate (600 g) in water (2.5 L), followed by water (3 L). The solvent was removed by evaporation under reduced pressure, toluene (1.0 L) added and the solution concentrated under reduced pressure to give the product as an oil (534 g).
Reaction SMILES: Cl.C([NH:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1)=O>CO>[NH2:4][C:5]1[N:10]=[C:9]([C:11](=[N:35][O:36][CH2:37][C:38]#[CH:39])[C:12]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH:22]([S:24][C:25]4[NH:26][N:27]=[N:28][N:29]=4)[CH3:23])[CH2:20][S:21][C@H:16]23)=[O:13])[CH:8]=[CH:7][CH:6]=1
Reactant: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Conc. Hydrochloric acid (0.43 ml.) was added to a solution of 7-[2-(6-formamidopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (2.35 g.) in methanol (15 ml.), and the mixture was stirred at ambient temperature for 30 minutes. The methanol was removed by distillation under reduced pressure from the reaction mixture, and the remaining aqueous solution was diluted with water (100 ml.) and then adjusted to pH 2 with an aqueous solution of sodium bicarbonate. The precipitating crystals were collected by filtration, washed with water and then dried to give 7-[2-(6-aminopyridin-2-yl)-2-propargyloxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer) (1.05 g.), m.p. 163°-165° C. (dec.).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([F:38])([F:37])[F:36])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH2:39])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>C(#N)C.CN(C=O)C>[Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:25]=4[C:35]([F:37])([F:36])[F:38])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH:39][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2OC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,4R)-4-(tert-Butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-amine (50 mg, 0.09 mmol) was dissolved in acetonitrile (716 μl). To this solution was added K2CO3 (12.4 mg, 0.09 mmol) and tert-butyl 2-bromoacetate (15.9 μl, 0.11 mmol). The resulting solution was stirred at room temperature overnight. This was diluted with DMF and filtered to remove solid material and was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give tert-butyl 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetate (LCMS [M+H]+=673.3), which was dissolved in CH2Cl2 (4 mL) and TFA (1.5 mL). This solution was stirred for 2 h before it was concentrated. The resulting residue was dissolved in 4 N HCl in dioxane (1.0 mL) and 6 N HCl aqueous solution (0.5 mL) and stirred overnight. Next, the reaction was stirred at 50° C. for 4 h. After cooling, the solution was mixed with MeCN and purified by preparative HPLC (Column: PHENOMENEX® Luna C18, 5-μm particles (30×100 mm; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15%-100% B over 10 minutes; Flow: 30 mL/min, uv detection 254 nM) to give 2-((3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetic acid, TFA salt Ex 67 (44.5 mg): LCMS [M+H]+=503.0; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (1H, dd, J=8.03, 1.65 Hz), 7.60-7.76 (8H, m), 5.17 (1H, d, J=4.18 Hz), 4.44-4.58 (2H, m), 4.06 (2H, d, J=2.64 Hz), 3.90-3.97 (1H, m); HPLC Peak RT=7 5 min (Analytical Method A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and (2R)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (first eluting compound of step 18.i, 8.0 g, 39.5 mmol) in 9-1 EtOH/H2O (240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([Cl:12])=[CH:7][N:6]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Sodium methoxide (295 mg, 5.45 mmol) was taken up in methanol (13.6 ml) and 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with 1:1 water:saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by Combiflash (0-10% diethyl ether/hexanes) afforded 280 mg (1.56 mmol, 57%) of 2,5-dichloro-4-methoxypyrimidine as a white solid.