Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([F:10])=[CH:8][C:7](F)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CS(C)=O>[CH3:1][O:2][C:3](=[O:25])[C:4]1[C:9]([F:10])=[CH:8][C:7]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[CH:6][C:5]=1[NH:12][C:13](=[O:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2[O:19][CH2:20][O:21][C:17]=2[CH:16]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(F)cc(F)cc1NC(=O)Cc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: COC(=O)c1c(F)cc(N2CCN(C)CC2)cc1NC(=O)Cc1ccc2c(c1)OCO2
Temperature: 80 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
To a solution of 2-(2-benzo[1,3]dioxol-5-yl-acetylamino)-4,6-difluoro-benzoic acid methyl ester (0.50 g, 1.43 mmol) in dimethylsulfoxide (8 mL) was added N-methylpiperazine (0.20 mL, 2.86 mmol). The reaction was stirred at 80° C. for 3 h then cooled at room temperature. The solid precipitated was filtered and washed with a mixture H2O/EtOH 1/1, to provide after drying the title compound (0.15 g, 25% yield).
Reaction SMILES: C(OC(C1C([O:24][C:25](=O)[C:26]([CH3:29])([CH3:28])[CH3:27])=C2C(C)=C(C)N(CC3C=CC=CC=3)C2=CN=1)=O)C.[CH2:31]([O:33][C:34]([C:36]1[C:37]([OH:48])=[C:38]2[C:44]([Br:45])=[C:43]([Br:46])[N:42]([CH3:47])[C:39]2=[CH:40][N:41]=1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([C:36]1[C:37]([O:48][C:25](=[O:24])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:38]2[C:44]([Br:45])=[C:43]([Br:46])[N:42]([CH3:47])[C:39]2=[CH:40][N:41]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2C
Reactant: CCOC(=O)c1ncc2c(c(C)c(C)n2Cc2ccccc2)c1OC(=O)C(C)(C)C
Product: CCOC(=O)c1ncc2c(c(Br)c(Br)n2C)c1OC(=O)C(C)(C)C

Procedure:
Prepared in analogy to that of 1-benzyl-4-(2,2-dimethyl-propionyloxy)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 2,3-Dibromo-4-hydroxy-1-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester. The title product, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.62 (s, 1H), 4.42 (q, 2H, J=7.0 Hz), 3.94 (s, 3H), 1.49 (s, 9H), 1.42 (t, 3H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][C:12]([F:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(F)cc2c1=O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (4.4 g, 18.7 mmol) in thionyl chloride (50 mL) was heated at reflux for 3 hours (at 30 min. mixture changed to a clear solution). The resultant solution was cooled to room temperature, and the excess thionyl chloride was evaporated in vacuo. The residue was added to ammonium hydroxide on ice (note: highly exothermic). Let resultant mixture stir for 15 minutes, and the product was collected by filtration and washed generously with water. The solid was purified by flash chromatography, on silica gel, eluted with a gradient of ethyl acetate (0% to 30%) in heptane, to give the product, 4.24 g (89%) as a colorless solid. MS: m/z 253.8 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[N+:18]([O-])=O)[CH2:7][CH2:8][CH3:9])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]([NH:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:12]=1[NH2:18])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)Nc1cc(C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCCC(CC(=O)OCC)Nc1cc(C)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
To a solution of 3-(5-Methyl-2-nitro-phenylamino)-hexanoic acid ethyl ester (1.4 g, 4.8 mmol) in MeOH (10 mL) was added a slurry of Pd/C (wet) (0.25 g) in MeOH. The reaction mixture was saturated with H2 balloon and stirred at room temperature for 2 h. When the reaction was complete, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated to afford 1.4 g of the desired product as dark purplish oil. This product was used for the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:24][NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[C:11]2[C:12]([CH2:20][CH:21]([OH:23])[CH3:22])=[CH:13][C:14]3[O:18][CH2:17][O:16][C:15]=3[CH:19]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[S:40]([O:23][CH:21]([CH3:22])[CH2:20][C:12]1[C:11]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:24][NH:25][C:26]2[N:27]=[CH:28][CH:29]=[CH:30][N:31]=2)=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)(=[O:42])(=[O:41])[CH3:39]
Reactant: CC(O)Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
2.35 g (5.58 mmol) of the compound prepared in Step A was dissolved in 50 ml of dry dichloromethane. The solution was cooled to 0° C. and after addition of 2.1 ml (15.07 mmol) of triethylamine 0.87 ml (11.22 mmol) of methanesulfonyl chloride was added over a period of 20 min, then the mixture was stirred at room temperature for 3 h. After washing with water it was dried and concentrated to yield 2.69 g (54%) of the title compound as an intermediate; Mp.: 122-124° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:17])[CH2:3][C:4]1[S:8][C:7](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]2[O:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>CS(C)=O>[OH:28][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=1)[CH2:27][N:1]([CH2:27][CH:26]([OH:28])[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:30])([F:29])[F:18])[CH:21]=1)[CH:2]([CH3:17])[CH2:3][C:4]1[S:8][C:7](/[C:9](/[CH3:16])=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(C2CO2)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(CC(C)N)s1
Solvent: CS(C)=O
Product: CCOC(=O)/C=C(\C)c1ccc(CC(C)N(CC(O)c2cccc(C(F)(F)F)c2)CC(O)c2cccc(C(F)(F)F)c2)s1

Procedure:
5 g of ethyl (E)-5-[(RS)-2-aminopropyl]-β-methyl-2-thiopheneacrylate and 3.7 g of m-(trifluoromethyl)phenylethylene oxide were stirred at 90° for 22 hours in 50 ml of dimethyl sulphoxide. A further 1.23 g of m-(trifluoromethyl)phenylethylene oxide were added and the mixture was heated to 90° for a further 19 hours. The working-up was carried out in analogy to Example 4. Chromatography on silica gel gave ethyl (E)-5-[(RS)-2-[bis-[(RS)-β-hydroxy-m-(trifluoromethyl)phenethyl]amino]propyl]-β-methyl-2-thiopheneacrylate; ε323 =17310.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]([C:21]([O:23]CC)=[O:22])=[CH:19][N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:13][N:14]([C:16]3[S:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]=3)[CH2:15]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CN(c3ncc(C(=O)O)s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 29 h
Yield: 52.9 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (217c) (65 mg, 0.17 mmol) was dissolved in methanol (2 mL). A 2 N aqueous lithium hydroxide solution (0.85 mL, 1.69 mmol) was added, and the mixture was stirred at room temperature for 29 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (1 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 32 mg of the title compound as a white solid (53%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22]O.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([O:15][CH2:22][CH:21]([O:24][CH3:25])[O:20][CH3:19])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: COC(CO)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)OC
Yield: 95 %

Procedure:
To a 100 mL, round bottom flask equipped with a magnetic stirrer and nitrogen inlet is added N-Benzyloxycarbonyl-L-proline (3.5 g), dichloromethane (25 mL) and 2,2-dimethoxyethanol (1.8 g). The mixture is cooled using an ice bath (0-5° C.) and DMAP (86 mg) is added. DCC (3.06 g) is added to the mixture over a period of 2 minutes. The resulting precipitate is filtered, washed with heptanes (2×10 mL) and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel chromatography using heptanes/ethyl acetate (4:1) as the eluent, and 4.5 g of 2,2-dimethoxyethyl N-benzyloxycarbonyl-L-prolinate was obtained.
Reaction SMILES: C1(C[O:8][C:9](=[O:27])[C:10]([CH3:26])([CH3:25])[CH2:11][CH2:12][O:13][C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:26][C:10]([CH3:25])([CH2:11][CH2:12][O:13][C:14](=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]([OH:27])=[O:8]
Reactant: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCC(C)(C)C(=O)O
Reaction time: 2 h
Yield: 96.6 %

Procedure:
A mixture of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid phenylmethyl ester (33.9 g), 20% Pd(OH)2 /C (2.0 g), and ethanol (150 mL) was hydrogenated at 50 psi at room temperature for 2 hours, filtered to remove the catalyst, and concentrated to afford 24.9 g (96.5%) of 2,2-dimethyl-4-[(1-oxodecyl)oxy]butanoic acid as a colorless oil. A portion was evaporatively distilled to afford an analytical sample: bp 190° C./0.02 mm; IR (CHC3) 1733 (C=O) and 1704 cm-1 (C=O); NMR (CDCl3) δ 0.87 (t, 3, CH3), 1.60-1.24 (m, 20, CH2 and CH3), 1.93 (t, 2, CH2), 2.25 (t, 2, CH2), 4.14 (t, 2, CH2); MS m/e 268 (M+ --H2O).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1
Reactant: Oc1ccc(Oc2cc3cc(Cl)ccc3nc2Cl)cc1
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(Oc2cc3cc(Cl)ccc3nc2Cl)cc1

Procedure:
Ethyl 2-{4-[(2,6-dichloroquinolin-3-yl)oxy]phenoxy}propionate was prepared by reacting 4-[(2,6-dichloroquinolin-3-yl)oxy]phenol and ethyl 2-bromopropionate following essentially the same procedure as that described in Example 1 part (c). The product was obtained as a solid, mp 56° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1>C(O)(=O)CC>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]2[C:17]3[NH:13][C:14]([C:9]([C:8]4[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=4)=[C:14]4[N:13]=[C:17]([C:9]([C:8]5[CH:11]=[CH:12][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=5)=[C:14]5[NH:13][C:17](=[C:9]([C:8]6[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=6)[C:14]6[CH:15]=[CH:16][C:17]=2[N:13]=6)[CH:16]=[CH:15]5)[CH:16]=[CH:15]4)=[CH:15][CH:16]=3)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: CC(=O)Nc1ccc(-c2c3nc(c(-c4ccc(NC(C)=O)cc4)c4ccc([nH]4)c(-c4ccc(NC(C)=O)cc4)c4nc(c(-c5ccc(NC(C)=O)cc5)c5ccc2[nH]5)C=C4)C=C3)cc1
Reaction time: 8 h

Procedure:
para-Acetamidobenzaldehyde (10.0g) is added to refluxing propionic acid (100ml): an orange solution gradually forms. Pyrrole (4.1g) is added continuously, and the dark solution is refluxed for 1 hour, and kept at 0° C. overnight. A dark tarry material is removed by filtration and the filtrate is evaporated to dryness. The residue is dissolved in chloroform and chromatographed on silica gel G eluted with 10% methanol in chloroform. The red fluorescing fractions are combined and the porphyrin HK9 is obtained as a purple solid (0.021g) on evaporation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:24]2)[CH:3]=1.CC[N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([NH2:35])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:24]2)[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3O[C@H]3CCCN(S(C)(=O)=O)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[4-Fluoro-2-((S)-1-methanesulfonyl-piperidin-3-yloxy)-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (120 mg) at 0° C. was added DIPEA (49 μl) followed by HATU (104 mg) and the solution was stirred for 30 min. A solution of ammonia in methanol (7M; 0.3 ml) was added and the solution allowed to warm to room temperature and stirred for 1 h. The solvent was evaporated and traces of DMF removed by co-evaporation with toluene. The residue was triturated with MeOH and the solid collected by filtration to give the desired product.
Reaction SMILES: [OH:1][C@@H:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C@@H:3]1[O:8][C@H:7]([CH3:9])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][C@@H:7]1[CH2:6][NH:5][CH2:4][C@H:3]([C@H:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:1])[O:8]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]([C@@H](O)c2ccccn2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CNC[C@H]([C@@H](O)c2ccccn2)O1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a stirred solution of (2R,6R)-tert-butyl 2-((S)-hydroxy(pyridin-2-yl)methyl)-6-methylmorpholine-4-carboxylate (150 mg, 0.486 mmol) in DCM (5 mL) was added TFA (1 mL) followed by stifling at rt for 1 h. The completed reaction was concentrated and azeotroped to dry three times with toluene (5 mL each) followed by diluting with DCM (10 ml) washing two times with saturated NaHCO3 in water (2 mL), brine (2 mL), drying over MgSO4, filtering and concentration and drying in vacuo to provide crude (S)-((2R,6R)-6-methylmorpholin-2-yl)(pyridin-2-yl)methanol (97.8 mg, 0.469, 96.4% yield).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([CH3:16])[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>CN(C=O)C>[CH3:16][C:5]1([CH2:4][O:3][C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[O:9][C:8]2=[N:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][N:7]2[CH2:6]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
Sodium hydride (77 mg, 1.9 mmol) was added to a solution of 2-hydroxymethyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 33 (0.32 g, 1.6 mmol) in DMF (3 ml) with cooling on ice-bath followed by stirring at 0° C. for 30 minutes. To the reaction mixture, 2-chlorobenzoxazole (0.30 g, 1.9 mmol) in DMF (3 ml) was added with cooling on ice-bath followed by stirring at room temperature for 44 hours. Ice-water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and recrystallized from acetonitrile-isopropanol to afford 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)benzoxazole (0.20 g, 39%) as a light yellow solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27]([N:30]1[CH2:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH2:32][CH2:31]1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH3:26][S:27]([N:30]1[CH2:31][CH:32]=[C:33]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)[CH2:34][CH2:35]1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (0.10 g), 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine (0.10 g), 2 M aqueous Na2CO3 solution (0.37 mL), and 1,4-dioxane (2 mL) is sparged with argon for 10 min. Tetrakis(triphenylphosphine)palladium(0) (20 mg) is added and the mixture is stirred in a microwave oven at 150° C. for 1.5 h. After cooling to room temperature, water and methanol are added and the resulting mixture is filtered. The filtrate is concentrated and the residue is chromatographed on reversed phase (HPLC, methanol/water) to give the title compound. LC (method 2): tR=1.63 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1>C(OCC)(=O)C>[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(CCCCCNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Note: N-benzyloxycarbonyl-6-aminohexanoic acid p-nitrophenyl ester was synthesized by standard techniques from N-benzyloxycarbonyl-6-aminohexanoic acid (Sigma Chemical Company), p-nitrophenol (Aldrich Chemical Company), and N,N1 -dicyclohexylcarbodiimide (Aldrich Chemical Company) in ethyl acetate solution.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]=O.[ClH:12]>O1CCCC1>[ClH:12].[CH3:10][NH:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1NC=O
Agent: Cl
Solvent: C1CCOC1
Product: CNc1c(C)cccc1C
Temperature: 25 °C

Procedure:
A suspension of 125.6 g. of 2,6-dimethylformanilide in 1100 ml. of dry tetrahydrofuran is cooled to 0° C. in ice-methanol. To this with constant stirring is added dropwise over a period of 3 hours 1125 ml. of 0.96 M BH3 in tetrahydrofuran. This is then allowed to warm gradually to room temperature and then heated slowly to reflux. Refluxing is maintained for 6 hours and then stirred at room temperature another 15 hours. The reaction mixture is then cooled in ice and acidified with 425 ml. of 6 N HCl. A white solid forms. The mixture is evaporated in vacuo and the water-solid slurry dissolved into 2 l. of water. The solution is made strongly alkaline (with cooling) with 50% NaOH and then extracted twice with ether (2 l.) The ether is then washed three times with 100 ml. portions of water and twice with 100 ml. portions of saturated sodium chloride solution. The ether is then dried over sodium sulfate, filtered, acidified with ethereal HCl while cooling. The white solid which forms is filtered, washed with ether and sucked dry. This is recrystallized from isopropanol:methanol to give N,2,6-trimethylaniline hydrochloride (m.p. 255-257 dec.)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24])(=O)C.C(Cl)(=O)C.C([O-])(O)=O.[Na+]>CO.C1COCC1>[NH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=2[F:19])[N:8]=[C:7]([C:20]([O:22][CH3:23])=[O:21])[C:6]=1[Cl:24]
Reactant: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)cc(NC(C)=O)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)Cl
Product: COC(=O)c1nc(-c2cc(F)c(Br)cc2F)cc(N)c1Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of methyl 4-acetamido-6-(4-bromo-2,5-difluorophenyl)-3-chloropicolinate (0.300 g, 0.715 mmol) in a mixture of MeOH (3.57 mL) and THF (3.57 mL) was slowly added acetyl chloride (1.017 mL, 14.30 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was then poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered, concentrated and dried in vacuo to afford methyl 4-amino-6-(4-bromo-2,5-difluorophenyl)-3-chloropicolinate (0.257 g, 0.681 mmol, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]#[N:28])=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Yield: 37.1 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (302 mg, 1.0 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (139 mg, 37%). MS (ISP) 375.0 [(M+H)+]; mp 184° C.