Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=O)[CH2:5][CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[N:16]([C:19]1[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[N+:17]=[N-:18].N1CCCC1.C([O-])(O)=O.[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[F:25][C:22]1[CH:21]=[N:20][C:19]([N:16]2[C:6]3[CH2:7][C@H:2]([CH3:1])[N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][C:5]=3[N:18]=[N:17]2)=[N:24][CH:23]=1
Reactant: C[C@H]1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ncc(F)cn1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: C[C@H]1Cc2c(nnn2-c2ncc(F)cn2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (2.76 g, 12.9 mmol) in toluene (100 mL) at 100° C. was added 2-azido-5-fluoropyrimidine (2.34 g, 16.8 mmol) as a solution in toluene (15 mL) followed by pyrrolidine (1.06 mL, 12.9 mmol). After stirring for 3 h at rt, the reaction was cooled to 0° C. and CH2Cl2 (100 mL) was added followed by NaHCO3 (2.17 g, 25.9 mmol) and mCPBA (4.47 g, 25.9 mmol). The reaction was allowed to warm to rt over 30 min followed by the addition of 1N NaOH (100 mL). The organic layer was separated and the water layer was extracted with CH2Cl2 two times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. Chromatography on silica gel (0-100% ethyl acetatehexanes) provided the desired product as a 9:1 mixture of regioisomers (9:1=(S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-6-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate: (S)-tert-butyl 1-(5-fluoropyrimidin-2-yl)-4-methyl-6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5(4H)-carboxylate (2.85 g, 66%). The minor regioisomer was separated by SFC (Chiralpak IC 5 μm 250*21 mm, mobile phase 70% CO2, 30% iPrOH) to provide the product as a white solid. MS (ESI) mass calcd. C15H19FN6O2, 334.16. m/z found, 335.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.73 (s, 2H), 5.16 (d, J=16.1 Hz, 1H), 4.96 (br s, 1H), 4.25 (d, J=16.4 Hz, 1H), 3.38-3.28 (m, 1H), 3.19-3.10 (m, 1H), 1.50 (s, 9H), 1.16 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:16](OC)(OC)(OC)[CH3:17]>C(O)(C(F)(F)F)=O>[CH:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:15])=[CH:4][CH:3]=[C:2]3[N:1]=[C:16]2[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(C)(OC)OC
Reactant: Nc1ccc(O)nc1NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(O)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
5-Amino-6-(cyclohexylamino) pyridin-2-ol (0.1 g, 0.482 mmol) was dissolved in trimethyl orthoacetate (3.0 mL, 27.4 mmol). Several drops of TFA were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residues were diluted with water/acetonitrile (1:1). The mixture was purified via HPLC to give the title compound (0.006 g). LCMS m/z=232.30 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.43-1.5 (m, 1H), 1.53-1.63 (m, 2H), 1.83 (d, J=11.87 Hz, 1H), 2.01 (d, J=10.99 Hz, 4H), 2.64-2.74 (m, 2H), 2.89 (s, 3H), 4.51-4.57 (m, 1H), 6.90 (d, J=8.8 Hz, 1H), 8.0 (d, J=8.8 Hz, 1H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15]O)[C:11](=[O:17])[O:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][Cl:20])[C:11](=[O:17])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(-n2oc(=O)n(CO)c2=O)c1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1cccc(-n2oc(=O)n(CCl)c2=O)c1

Procedure:
2-(3-Methylthiophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(3-methylthiophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Br:23])[CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[K+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:18][C:17]2[CH:20]=[CH:21][C:22]([Br:23])=[C:15]([Br:14])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Br)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (3.5 g) and 3,4-dibromobenzaldehyde (5.0 g) in DCM (80 mL) was treated with NaB(OAc)3H (5.6 g). After 16 h, the resulting mixture was treated with 10% aq. KOH (80 mL). The aqueous phase was extracted with DCM (1×80 mL). The organic extracts were combined and dried (MgSO4). Most of the solvent was removed by concentration. Upon standing overnight, the resulting mixture produced crystals that were filtered and washed with DCM (1×5 mL), giving the title compound as a white crystalline solid (6.0 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[C:17]1([S:23]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[CH:31]=O)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:31][C:27]2[N:28]=[CH:29][S:30][C:26]=2[S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:24])=[O:25])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ncsc1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: COC(=O)Cn1c(C)c(Cc2ncsc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 5-benzenesulfonylthiazole-4-carbaldehyde in dichloromethane.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:6]=1[CH:7]([CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:30][N:31]([C:13]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:7]([C:6]2[CH:5]=[C:4]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:3][C:2]=2[CH3:1])[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:17][CH:16]=1)=[O:15])[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCOC(=O)CCNC
Reactant: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1oc(-c2ccccc2)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A solution of 4-[(2-methyl-5-phenylfuran-3-yl)(tetrahydro-2H-pyran-4-yl)methoxy]benzoic acid (177 mg), ethyl 3-(methylamino)propanoate (66 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg), hydroxybenzotriazole monohydrate (77 mg) and triethylamine (70 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (61 mg, 29%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]3[N:16]=[CH:17][S:18][C:12]=3[N:11]=[C:10]2S)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:14](=[O:15])[C:13]2[N:16]=[CH:17][S:18][C:12]=2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2ncsc2nc(S)n1-c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Product: O=c1c2ncsc2nc(Cl)n1-c1ccc(F)cc1
Temperature: 135 °C

Procedure:
6-(4-Fluorophenyl)-5-mercapto[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one hydrochloride (0.2 g, 0.633 mmol) is added to POCl3 (10 mL), and the resulting solution is refluxed at 135° C. for 41 h. Most of the volatiles are removed under reduced pressure and the residual solvent is co-evaporated with toluene (50 mL×3). The dark solid obtained is dissolved in CH2Cl2 (200 mL) and washed with saturated NaHCO3 solution (100 mL×5), brine (50 mL×2), and dried over MgSO4. After removing solvent, silica gel column chromatography (EtOAc:hexanes=50:50) yields the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) 8.88 (1H, s), 7.26 (4H, m).
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[CH3:29][O:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[CH:34]=[C:33]([C:39](O)=[O:40])[N:32]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:39]([C:33]2[CH:34]=[C:35]([O:37][CH3:38])[N:36]=[C:31]([O:30][CH3:29])[N:32]=2)=[O:40])[CH2:26][CH3:27])[CH:13]=1)[CH3:4]
Reactant: COc1cc(C(=O)O)nc(OC)n1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)c2cc(OC)nc(OC)n2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and 2,4-dimethoxypyrimidine-6-carboxylic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-(2,6-dimethoxy-pyrimidine-4-carbonyl)-N-ethyl-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 8, Step 7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:17](=[O:19])[CH3:18])[CH:8]2[CH3:20])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:17](=[O:19])[CH3:18])[CH:8]2[CH3:20]
Reactant: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1C
Agent: [Pd]
Solvent: CCO
Product: CC(=O)N1c2ccccc2-c2c(N)cnn2C1C
Yield: 84.6 %

Procedure:
27.1 g (0.1 mole) of 1-nitro-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are hydrogenized in ethanol in the presence of palladium/carbon catalyst. When the reduction is complete, the catalyst is removed by filtration and the filtrate is evaporated in an inert atmosphere under reduced pressure. 20.5 g (81%) of 1-amino-5-methyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline are obtained as white crystals. M.p.: 170°-172° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][N:7]([C:16]([C@@:18]1([CH3:33])[CH2:21][CH2:20][N:19]1[C:22]([C:24]1[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[S:27][CH:28]=1)=[O:23])=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1.[OH-].[Na+]>CO>[S:27]1[CH:28]=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][C@:18]2([CH3:33])[C:16]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH2:6][CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[O:17])=[O:23])[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]1=2
Reactant: COC(=O)CCCN(Cc1cccc(Cl)c1)C(=O)[C@@]1(C)CCN1C(=O)c1csc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@]1(C(=O)N(CCCC(=O)O)Cc2cccc(Cl)c2)CCN1C(=O)c1csc2ccccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
To a solution of 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester, Intermediate 112 (25 g, 1 eq.) in 750 mL of MeOH was added aqueous NaOH (2N) (75 mL, 3 eq.). The reaction was stirred at 20° C. for 15 h. The solvent was removed under reduced pressure and the crude was partitioned between water and EtOAc. The organic layer was discarded. The aqueous layer was acidified by addition of HCl (2N) until pH=2 and thoroughly extracted three times with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to afford 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid (23.7 g, yield=97%).
Reaction SMILES: CS(OC)(=O)=O.[NH2:7][C:8]1[N:9]=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[C:12]([NH2:14])[N:13]=1.[CH3:23]N(C)C=O>C1(C)C=CC=CC=1>[NH2:14][C:12]1[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[N:10][N:9]([CH3:23])[C:8](=[NH:7])[N:13]=1
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Reactant: CN(C)C=O
Agent: COS(C)(=O)=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cccc(Cl)c2Cl)c(N)nc1=N
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Methyl methanesulfonate (0.50 g, 4.5 mmol), 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (0.50 g, 2.0 mmol) and dimethylformamide (4 ml) were stirred and heated at 100° C. for 10 min. The solution was cooled, toluene (20 ml) added, and the mixture stirred for 0.5 h. The solid was collected by filtration and recrystallised from propan-2-ol to give the methanesulfonate salt of the title compound as a white solid (0.40 g), mp 274-276° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([O:26]C)[N:25]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([OH:26])[N:25]=1)[C:13]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)NCc2ccccc2)cc(NC(=O)c2ccccc2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(NCc1ccccc1)c1cc(O)nc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
To a solution of 2-benzamido-N-benzyl-6-methoxyisonicotinamide (0.18 g, 0.50 mmol) and sodium iodide (0.45 g, 3.00 mmol) in acetonitrile (10 mL) was added chlorotrimethylsilane (0.39 mL, 3.00 mmol) and water (0.1 mL) at 0° C. The resulting solution was stirred at ambient temperature for 20 hours, quenched with methanol (10 mL), stirred for 10 minutes and concentrated in vacuo. The residue was washed with saturated sodium bicarbonate solution (5 mL) and water (5 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo to a minimum volume and triturated with ethyl acetate. The solid was filtered and dried in vacuo to give 2-benzamido-N-benzyl-6-hydroxyisonicotinamide as a colorless solid (0.04 g, 20%): mp 257° C. (dec); 1H NMR (300 MHz, DMSO-d6) δ 11.07 (br s, 1H), 9.20 (br s, 1H), 8.46-6.59 (m, 12H), 4.37 (br s, 2H); MS (ES+) m/z 348.5 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:9]3)[CH:5]=[CH:6][CH:7]=1.CO>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C@:8]23[CH2:17][CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[N:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cccc(Br)c3)CCOCC2CS1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cccc(Br)c3)CCOCC2CS1
Yield: 46.8 %

Procedure:
Racemic tert-butyl (4aSR,8aSR)-8a-(3-bromophenyl)-4,4a,5,7,8,8a-hexahydropyrano[4,3-d][1,3]thiazin-2-ylcarbamate (2.80 g, 6.55 mmol) is purified by chiral HPLC: Column: Chiralcel OJ 8×35 cm; eluent: 75:25 (methanol:acetonitrile); flow: 400 mL/min at UV 260 nm. The second eluting isomer is isolated to provide the enantiomerically enriched title compound (1.31 g, 47%). ES/MS m/e (79Br/81Br) 427, 429 (M+1).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12](OC)=[O:13])#[N:6]>CS(C)=O.O>[CH:1]1([NH:4][C:12](=[O:13])[C:11]2[CH:16]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=2[OH:17])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: NC1CC1
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(O)c(C(=O)NC2CC2)c1
Temperature: 80 °C

Procedure:
Cyclopropyl amine (14.3 g) and Na (100 mg) were added to a solution of methyl 5-cyano-2-hydroxybenzoate (10.0 g; from step (b) above) in DMSO (40 mL). The reaction mixture was heated at 80° C. in a sealed steel vessel overnight, diluted with H2O, acidified and extracted with EtOAc giving the sub-title compound (11.0 g), after concentration of the organic layer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCN1CCOCC1)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 1.1 g, 5.00 mmol) was dissolved in DCM (10 mL) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) added. The mixture was cooled in an ice/water bath and 4-(2-aminoethyl)morpholine (Aldrich; 0.66 mL, 5.00 mmol) in DCM (5 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was washed with brine, 2N NaOH, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeoH/DCM) gave the title compound as a yellow solid. (1.2 g, 76%)
Reaction SMILES: CC1(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2N(CCCS([O-])(=O)=O)/C/1=C/C=C(\C1C=CC=C(CCCCC([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH2:83][CH2:82][C:81]2=[O:86])=O)C=1)/C=C/C1C(C)(C)C2C3C=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C=3C=CC=2[N+]=1CCCS([O-])(=O)=O.[Na+:88].[Na+].[Na+].[Na+].[Na+].[CH3:93][C:94]1([CH3:177])[C:102]2[C:101]3[CH:103]=[C:104]([S:111]([O-:114])(=[O:113])=[O:112])[CH:105]=[C:106](S([O-])(=O)=O)[C:100]=3[CH:99]=[CH:98][C:97]=2[N:96]([CH2:115][CH2:116][CH2:117][CH2:118][S:119]([O-:122])(=[O:121])=[O:120])/[C:95]/1=[CH:123]/[CH:124]=[C:125](\[C:159]1[CH:164]=[CH:163][CH:162]=[C:161]([CH2:165][CH2:166][C:167](ON2C(=O)CCC2=O)=[O:168])[CH:160]=1)/[CH:126]=[CH:127]/[C:128]1[C:136]([CH3:138])([CH3:137])[C:135]2[C:134]3[CH:139]=[C:140](S([O-])(=O)=O)[CH:141]=[C:142]([S:143]([O-:146])(=[O:145])=[O:144])[C:133]=3[CH:132]=[CH:131][C:130]=2[N+:129]=1[CH2:151][CH2:152][CH2:153][CH2:154][S:155]([O-:158])(=[O:157])=[O:156].[Na+].[Na+].[Na+].[Na+].[Na+]>>[CH3:137][C:136]1([CH3:138])[C:135]2[C:134]3[CH:139]=[C:140]([S:111]([O-:114])(=[O:113])=[O:112])[CH:141]=[C:142]([S:143]([O-:146])(=[O:144])=[O:145])[C:133]=3[CH:132]=[CH:131][C:130]=2[N:129]([CH2:151][CH2:152][CH2:153][CH2:154][S:155]([O-:158])(=[O:156])=[O:157])/[C:128]/1=[CH:127]/[CH:126]=[C:125](\[C:159]1[CH:164]=[CH:163][CH:162]=[C:161]([CH2:165][CH2:166][C:167]([NH:77][CH2:78][CH2:79][N:80]2[C:84](=[O:85])[CH:83]=[CH:82][C:81]2=[O:86])=[O:168])[CH:160]=1)/[CH:124]=[CH:123]/[C:95]1[C:94]([CH3:93])([CH3:177])[C:102]2[C:101]3[CH:103]=[C:104]([S:111]([O-:114])(=[O:113])=[O:112])[CH:105]=[C:106]([S:119]([O-:122])(=[O:121])=[O:120])[C:100]=3[CH:99]=[CH:98][C:97]=2[N+:96]=1[CH2:115][CH2:116][CH2:117][CH2:118][S:119]([O-:122])(=[O:120])=[O:121].[Na+:88].[Na+:88].[Na+:88].[Na+:88].[Na+:88]
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)ON3C(=O)CCC3=O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCCCC(=O)NCCN3C(=O)CCC3=O)c2)=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCCS(=O)(=O)[O-])c3ccc4c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc4c3C2(C)C)c2cccc(CCC(=O)NCCN3C(=O)C=CC3=O)c2)=[N+](CCCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c21

Procedure:
Compound 22 is prepared analogously to compound 21 (Example 27), except that compound 11 is used as a starting material.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]([OH:24])([CH3:23])[CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]2=[O:22])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].O1CCOCC1>O>[CH3:23][C:11]1([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][C:14]2=[O:22])[O:24][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(O)(Cn1cc([N+](=O)[O-])nc1Cl)Cn1c(=O)oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(Cn2c(=O)oc3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Yield: 38 %

Procedure:
A mixture of 3-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-3H-benzoxazol-2-one prepared in Example 541 (615 mg, 1.74 mmol), sodium hydride (76.6 mg, 1.91 mmol), 1,4-dioxane (15 ml) was stirred under reflux for 1 hour. The reaction mixture was allowed to return to room temperature. To the solution, water was added and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-3H-benzoxazol-2-one (209 mg, yield 38%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: Nc1ncccc1CO
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ncc(Br)cc1CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78 %

Procedure:
To a solution of 2-amino-3-(hydroxymethyl)pyridine (13.0 g, 116.0 mmole) in CH2Cl2 (300 mL) at RT was added NBS (22.71 g, 127.6 mmole). After stirring at RT for 45 min the reaction solution was concentrated and the residue was dissolved in CHCl3. The resulting suspension was filtered and the filtrate was concentrated to a dark oil. Purification on silica gel (EtOAc) afforded the title compound (78%, 18.36 g) as a tan solid: MS (ES) m/e 204 (M+H)+.