Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8](=[N:16][OH:17])[C:9]([CH3:15])(S(C)(=O)=O)[CH3:10])=O)C.[OH-].[NH4+:19].N>O>[N:16](=[C:8]1[C:9]([CH3:15])([CH3:10])[NH:19][C:4](=[O:3])[CH2:6][S:7]1)[OH:17]
Reactant: [NH4+]
Reactant: CCOC(=O)CSC(=NO)C(C)(C)S(C)(=O)=O
Agent: N
Agent: [OH-]
Solvent: O
Product: CC1(C)NC(=O)CSC1=NO
Temperature: 25 °C

Procedure:
A mixture of 5.0 g 1-(ethoxycarbonylmethylthio)-2-methyl-2-(methylsulfonyl)propionaldoxime and 150 ml. of ammonium hydroxide was charged into a pyrex pressure bottle and stirred at room temperature for forty hours. The mixture was stripped of excess ammonia and water under reduced pressure. The solid crystalline residue was washed with water, then dried at room temperature to yield 3 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 234° C. The nmr spectrum was identical with those of the compounds from Examples II and III.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.C[O-].[Na+]>CO>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OCCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a solution of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}-benzofuran (20 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 0.006 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (14 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:23])=[O:22]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:15]2[C:16]([S:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])(=[O:22])=[O:23])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][C:5]=1[F:13])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1F
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Product: CCN(CC)S(=O)(=O)c1ccccc1-c1ccc(C(C)=O)c(F)c1

Procedure:
The title compound was prepared using conditions analogous to those described in Example 1 using (4-acetyl-3-fluorophenyl)boronic acid and 2-bromo-N,N-diethylbenzenesulfonamide. MS (ESI): mass calcd. for C18H20FNO3S, 349.11; m/z found, 350.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J=7.9, 1.2, 1H), 7.92 (m, 1H), 7.61-7.56 (m, 1H), 7.55-7.49 (m, 1H), 7.29-7.27 (m, 2H), 7.25-7.24 (m, 1H), 2.95 (q, J=7.1, 4H), 2.69 (d, J=4.9, 3H), 1.01 (t, J=7.1, 6H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:40](=[O:41])[C:39]2[CH:38]=[CH:37][C:36]([N+:33]([O-:35])=[O:34])=[CH:44][CH:43]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCN1[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -5 °C
Yield: 62.1 %

Procedure:
Dissolve 1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (144 g, 0.79 mol) in dry tetrahydrofuran (5 L) and cool to −5° C. under nitrogen. Add triphenylphosphine (310 g, 1.185 mol) and 4-nitrobenzoic acid (198 g, 1.185 mol). Add diisopropyl azodicarboxylate (230 mL, 1.185 mol) drop-wise and stir at room temperature overnight. Add saturated aqueous sodium bicarbonate (IL) and extract into dichloromethane (2×2.5 L) in a 20 L separating funnel. Dry the combined organic layers over magnesium sulfate, filter and concentrate. Purify over silica gel (iso-hexane/ethyl acetate 50-100% then 10% methanol in ethyl acetate) to afford 163 g (62%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:9]=[C:8]2[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21](CC3C=CC=CC=3)[CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+]>CO.[Pd]>[C:1]1([N:7]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:9]=[C:8]2[O:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCC(COc3nc4c(n3-c3ccccc3)CCCC4)CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1ccc(-n2c(OCC3CCNCC3)nc3c2CCCC3)cc1
Yield: 72 %

Procedure:
0.98 g (2.44 mmol) of 1-phenyl-[[1-(phenylmethyl)piperidin-4-yl]methoxy]-4,5,6,7-tetrahydro-1H-benzimidazole is suspended in 20 ml of methanol and supplemented successively with 1.54 g (2.44 mmol) of ammonium formate and 0.75 g of 10% palladium on carbon. The mixture is heated at boiling temperature for 1 hour, filtered and concentrated under vacuum. The product is taken up in 5 N sodium hydroxide, extracted with methylene chloride and dried over Na2SO4. After concentration, 0.55 g of product is recovered. Yield=72%.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH:9]([CH2:32][O:33]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[C:1]1([CH2:7][O:8][CH:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:14][CH:13]=2)[CH2:32][OH:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCc1ccc(OCC(CO)OCc2ccccc2)cc1

Procedure:
An about 14.6 g portion of 1-[2-(phenylmethoxy)-3-(triphenylmethoxy)propoxy]-4-tetradecylbenzene was dissolved in about 50 ml of tetrahydrofuran. To this solution was added about 50 ml of methanol and about 100 mg of p-toluenesulfonic acid. The mixture was stirred under argon for several hours and the solvents were then removed. The residue was dissolved in ether, washed with aqueous sodium bicarbonate, dried and the ether evaporated. The residue was purified by chromatography on silica gel, eluting with hexane:ether (about 12:1), giving about 7.6 g of the desired title compound, mp 50°-51° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([C:37]1[CH:38]=[CH:39][C:40]([C:43]([F:46])([F:44])[F:45])=[CH:41][CH:42]=1)[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(C(F)(F)F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccc(C(F)(F)F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-[3-(1-{5-hydroxy-5-[4-(trifluoromethyl)phenyl]pentyl}-4-piperidinyl)phenyl]-2-methylpropanamide: ESMS m/e: 639.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([OH:20])=O)[C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[CH2:1]([N:8]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:20])[C:9]([CH:11]1[CH2:12][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1
Product: CC(C)(C)NC(=O)c1ccc(Br)c(CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
3-[(N-Benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-benzoic acid and tert-butylamine were reacted as described in Example 5, Step 6 to provide 3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-bromo-N-tert-butyl-benzamide
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([OH:22])[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:22][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)O)C(=O)OCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(=O)C(=CNc1ccccc1C(C)OC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate (63 g, 0.2 mol) and pyridine (50 ml) in dichloromethane (400 ml) were stirred at 0° C. and treated with benzoyl chloride (50 ml) in dichloromethane (100 ml) added at such a rate to keep the reaction temperature below 10° C. The cooling bath was removed and the mixture was stirred at ambient temperature for 2 hours. The solution was washed with 2M hydrochloric acid (x2), saturated sodium hydrogen carbonate solution, water and brine, dried (anhyd. MgSO4), filtered and evaporated to an orange oil (70 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:23]2[CH:24]=[CH:25][NH:26][C:27]=2[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2[nH]cc(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 5-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol, 1-chloro-3-(1H-indole-4-oxy)propane (0.45 g, 2.2 mmol and potassium carbonate (0.35 g, 2.5 mmol). The product was isolated as a white foam. Yield 220 mg (25%). mp 198°-202° C. FDMS m/e=406 (M+ of free base).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]\[C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.O.O[N:27]1[C:31]2[CH:32]=CC=C[C:30]=2N=N1.C(N(C(C)C)C(C)C)C.C(N)(C)C.[Cl-].[Na+]>CN(C=O)C>[CH:31]([NH:27][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15](/[CH:14]=[CH:13]\[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])([CH3:32])[CH3:30]
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)O)n(C)n1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)N
Solvent: O
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C\c1cc(C(=O)NC(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of 5-{(Z)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2-methyl-2H-pyrazole-3-carboxylic acid (0.3 mmol) in DMF (7 mL) was added 1-hydroxybenzotriazole hydrate (0.45 mmol), N-ethyldiisopropylamine (1.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidazole hydrochloride 0.45 mmol) and isopropylamine (27.8 mg, 0.45 mmol) and the resulting mixture stirred overnight at room temperature. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and saturated sodium hydrogen carbonate solution and then dried over sodium sulfate, filtered and evaporated. Concentration and purification by preparative HPLC afforded the title compound (35 mg, 28%) as an off white gum. MS: m/e=369.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:7])[CH2:4][O:5][CH3:6].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.O>C1C=CC=CC=1>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]2[NH:1][CH2:2][CH:3]([CH2:4][O:5][CH3:6])[O:7]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COCC(O)CN
Solvent: O
Solvent: c1ccccc1
Product: COCC1CNC(c2ccc(Cl)cc2)O1
Temperature: 25 °C

Procedure:
Twelve and six tenths (12.6) grams of 1-amino-3-methoxy-2-propanol and 16.9 grams of p-chlorobenzaldehyde were combined in 150 milliliters of benzene and heated to reflux under a modified Dean-Stark apparatus until about 2.5 milliliters of water were azeotropically removed. An additional 50 milliliters of benzene was distilled over and the mixture was cooled to room temperature and the volume was adjusted to 109.2 milliliters, so that 4 milliliters=1 gram of intermediate. Aliquots of this solution were used in subsequent reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:26])[NH:22][CH2:23][CH:24]=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:13][C@H:12]1[C:21]1[O:26][CH:24]=[CH:23][N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)NCC=O)N(C(=O)OCc2ccccc2)C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)O[C@@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a stirred solution of (2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (4.5 g, 12.43 mmol) and hexachloroethane (5.88 g, 24.86 mmol) in dichloromethane (30 mL) was added triphenyl phosphine (6.52 g, 24.86 mmol) The mixture was stirred at 0° C. for 15 min, triethylamine (2.5 g, 24.86 mmol) was then added and the mixture was stirred at room temp. for 14 h. The reaction mixture was then extracted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (using 15% EtOAc in hexane as eluent) to give (2S,4R)-4-tert-butoxy-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester (2 g, 46.6% yield) as a yellow liquid. MS calcd. for C19H25N2O4 [(M+H)+] 345.0, obsd. 345.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=1[C:12]([O:14]C)=O)=[O:8])[CH3:2].CC([O-])(C)C.[K+].O.Cl>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][C:7](=[O:8])[NH:9][C:10]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:11]=2[C:12]1=[O:14])=[O:21])[CH3:2]
Reactant: CCOC(=O)CCC(=O)Nc1ccc(I)cc1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CC(=O)Nc2ccc(I)cc2C1=O
Reaction time: 2.5 h

Procedure:
To a solution of methyl 2-(4-ethoxy-4-oxobutanamido)-5-iodobenzoate (ii-a) (22.0 g, 54 mmol) in 125 mL of THF was added a 1 M solution of KOt-Bu in THF (119 mL, 119 mmol). The reaction was complete after 2.5 h at 22° C. H2O (250 mL) and 1N HCl (60 mL) were added to the solution, and the resulting precipitate was filtered, washed with 2×50 mL Et2O, and dried in vacuo to give iii-a (16.1 g, 83%) as a whitish/gray solid as a mixture of ethyl and methyl esters: MS m/z═374 (M+H) and 360 (M+H).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[C:5]([OH:7])=O)=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:56])[C:30]=1[CH2:31][CH2:32][C@H:33]1[O:38][CH2:37][C@H:36]([CH2:39][O:40][C:41]([NH:43][CH2:44][C:45]([F:48])([F:47])[F:46])=[O:42])[N:35]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:34]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([NH:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([F:56])[C:30]=1[CH2:31][CH2:32][C@H:33]1[O:38][CH2:37][C@@H:36]([CH2:39][O:40][C:41](=[O:42])[NH:43][CH2:44][C:45]([F:48])([F:46])[F:47])[N:35]([C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[CH2:34]1)=[O:7])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cncc2F)OC[C@@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1cc(F)cc(F)c1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(F)cncc2NC(=O)[C@@H](N=[N+]=[N-])[C@@H](c2ccc(Cl)cc2)c2cc(F)cc(F)c2)OC[C@H]1COC(=O)NCC(F)(F)F
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (105 mg, 0.31 mmol) and the product from step 4 of Example 89 (150 mg, 0.31 mmol) were dissolved in pyridine (1 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.035 mL, 0.38 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (1 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined dichloromethane phases were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-70% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H)+=800.6.
Reaction SMILES: [Li]C(CC)C.CN(CCN(C)C)C.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1.O>[Cl:25][C:16]1[C:15]([Cl:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
sBuLi (97 mL, 126 mmol) was dissolved in tetrahydrofuran (THF) (200 mL) at −78° C. and TMEDA (19.02 mL, 126 mmol) was added. 3-chloro-4-fluorobenzoic acid (10 g, 57.3 mmol, commercially available from e.g. Sigma-Aldrich, Fluorochem or Apollo) dissolved in tetrahydrofuran (THF) (50 mL) was added dropwise at −78° C. and the solution stirred at this temperature for 30 minutes. Hexachloroethane (54.2 g, 229 mmol) dissolved in tetrahydrofuran (THF) (200 mL) was added dropwise and the solution stirred to room temperature over 4 hours. Water (25 mL) was added and the solution concentrated in vacuo. The residue was partitioned between diethyl ether (300 mL) and saturated sodium bicarbonate solution (50 mL) and extracted with saturated sodium bicarbonate solution (3×50 mL). The aqueous phase was acidified to pH1 with 5N hydrochloric acid, extracted with diethyl ether (3×200 mL), combined extracts dried over anhydrous magnesium sulfate and concentrated in vacuo to afford a crude solid (9.21 g). The crude solid was recrystalised from heptane/diethyl ether to afford the desired product in 4.91 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](O)=[O:11]>C1COCC1>[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[CH2:10][OH:11]
Reactant: Nc1cccc(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO410H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M−OH]+: 124.1; tR=0.57 min. (method 1)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[N+:25]([O-])([OH:27])=[O:26].S(=O)(=O)(O)O>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:14][C:13]([N+:25]([O-:27])=[O:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COCCOc1c(OC(=O)c2ccccc2)cccc1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COCCOc1c(OC(=O)c2ccccc2)cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Methyl 2-{[2-(methyloxy)ethyl]oxy}-3-[(phenylcarbonyl)oxy]benzoate (8.0 g, 24.2 mmol) was added drop wise over 15 minutes to a mixture of 90% nitric acid (15 mL) and concentrated sulfuric acid (3 mL) at −5° C. The resulting mixture was stirred for an additional 15 minutes then it was poured into a mixture of ice (200 g) and dichloromethane (200 mL). The organic portion was separated, washed with saturated sodium bicarbonate solution, brine (100 mL each) dried over sodium sulfate, filtered and concentrated to give methyl 2-{[2-(methyloxy)ethyl]oxy}-5-nitro-3-[(phenylcarbonyl)oxy]benzoate (8.1 g, 21.6 mmol, 89% yield). 1H NMR (400 MHz, CDCl3): 8.63-8.62 (d, 1H), 8.27-8.26 (d, 1H), 8.21-8.19 (m, 2H), 7.69-7.67 (d, d, 1H), 7.55-7.51 (d, d, 2H), 4.26-4.24 (m, 2H), 3.96 (s, 3H), 3.58-3.56 (m, 2H), 3.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH2:11][N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH:17]=O)=[C:5]([N+:19]([O-])=O)[CH:4]=1.C(O)(=O)C.S([O-])([O-])(=O)=O.[Mg+2]>[Pd].C(OCC)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[NH:19][CH2:17][C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:6]=2[CH:7]=1
Reactant: COc1cc(Cn2cccc2C=O)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)NCc1cccn1C2
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of the 1-[(4,5-dimethoxy-2-nitrophenyl)methyl]-1H-pyrrole-2-carboxaldehyde of Step A (4.97 g), acetic acid (0.5 mL), magnesium sulfate (0.5 g) and 10% palladium on charcoal (0.5 g) in ethyl acetate (50 mL) was hydrogenated overnight at atmospheric pressure. The reaction was then filtered through Celite and the solvent removed in vacuo to give the crude title compound as an amber foam (3.2 g) which was used in the next step without further purification.
Reaction SMILES: C([NH:14][P:15]([CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)(=[O:17])[OH:16])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>>[NH2:14][P:15]([CH2:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)(=[O:16])[OH:17]
Reactant: O=P(O)(Cc1ccsc1)NC(c1ccccc1)c1ccccc1
Agent: Cl
Product: NP(=O)(O)Cc1ccsc1
Temperature: 0 °C

Procedure:
A mixture of 15 g of the compound from step 1 and 122 ml of 6N HCl is boiled under reflux for 2 hours. After cooling, the reaction medium is concentrated by half and extracted with 3×1.5 l of ethyl ether. The solution is evaporated to dryness and the oily residue is taken up with 120 ml of ethanol. The solution is cooled to 0° C. and 30 ml of propylene oxide is added. A white solid precipitates. The precipitate is dewatered, washed with ethanol (2×20 ml), ethyl ether (2×10 ml) and dried. White solid, 7.32 g (95.1%).